Cyclopentylacrylamide derivative

ABSTRACT

A compound having a hypoglycemic effect is provided. The compound and a pharmaceutically acceptable salt thereof are useful for the treatment or prevention of diabetes, obesity, and the like. The compound is represented by the general formula (1): 
     
       
         
         
             
             
         
       
     
     (wherein R 1  and R 2  are each independently a hydrogen atom, a halogen atom, an amino group, a hydroxyl group, a hydroxyamino group, a nitro group, a cyano group, a sulfamoyl group, a C 1  to C 6  alkyl group, a C 1  to C 6  alkoxy group, a C 1  to C 6  alkylsulfanyl group, a C 1  to C 6  alkylsulfinyl group, a C 1  to C 6  alkylsulfonyl group, or a C 1  to C 6  alkoxy-C 1  to C 6  alkylsulfonyl group, and A is a substituted or unsubstituted heteroaryl group).

TECHNICAL FIELD

The present invention relates to an activator of glucokinase (which maybe abbreviated as GK). The present invention also relates to apharmaceutical composition for the treatment or prevention of diabetes,obesity, and the like that contain the GK activator as an activeingredient.

BACKGROUND ART

According to a patient survey conducted by the Japanese Ministry ofHealth, Labor and Welfare in Heisei 14 (2002), the total number ofdiabetes patients in Japan was 2.28 million. Moreover, according to adiabetes survey conducted in the same year, the total number of people“strongly suspected of having diabetes” and people in whom “thepossibility of diabetes cannot be denied” had increased to 16.20million, and this increase has been perceived as a problem.

Since the insulin secretory capacity of Japanese is low due to geneticfactors, the Japanese domestic market is mainly for impaired insulinsecretion. However, due to the westernization of Japanese dietaryhabits, the number of patients with insulin resistance is graduallyincreasing in recent years. Accordingly, there is a demand for drugsthat are expected to be effective for both impaired insulin secretionand insulin resistance.

Glucokinase (GK), which catalyzes the phosphorylation of glucose,functions as a glucose sensor in the body and increases glucoseutilization in the liver and the secretion of insulin in a high glucosestate. In diabetes patients, the homeostasis of glucose concentration inthe body is not maintained in a normal state. Therefore, by activatingGK, insulin secretion from the pancreas, which depends on theconcentration of glucose, is facilitated. In the lever, the activationof GK increases the glucose utilization and suppresses glucose output.This dual action reduces the blood glucose level (Non-Patent Documents 1to 3). Therefore, it is desirable to provide GK activators useful asdiabetes drugs that are effective for both impaired insulin secretion(action in the pancreas) and insulin resistance (action in the liver).

Various amide compounds are known as GK activators. Examples of suchamide compounds include: aryl cycloalkyl propionamides (Patent Document1); 2,3-di-substituted trans olefinic N-heteroaromatic or ureidopropionamides (Patent Document 2); alkynyl phenyl heteroaromatic amides(Patent Document 3); hydantoins (Patent Document 4); substitutedphenylacetamides (Patent Document 5); para-alkyl, aryl, cycloheteroalkylor heteroaryl (carbonyl or sulfonyl) amino substituted phenyl amides(Patent Document 6); alpha-acyl and alpha-heteroatom-substituted benzeneacetamides (Patent Document 7); tetrazolyl-phenyl acetamides (PatentDocument 8); fused heteroaromatic compounds (Patent Document 9);phenylacetamides having a cycloalkane with a single carbon atomsubstituted or a heterocycle (Patent Document 10); and other amidecompounds (Patent Documents 11 to 21). However, these patent documentsdo not disclose acrylamide compounds in which two fluorine atoms areattached to different carbon atoms of a cyclopentyl group.

PRIOR ART DOCUMENT Patent Document

-   [Patent Document 1] WO2000/058293 pamphlet-   [Patent Document 2] WO2001/044216 pamphlet-   [Patent Document 3] WO2001/083465 pamphlet-   [Patent Document 4] WO2001/083478 pamphlet-   [Patent Document 5] WO2001/085706 pamphlet-   [Patent Document 6] WO2001/085707 pamphlet-   [Patent Document 7] WO2002/008209 pamphlet-   [Patent Document 8] WO2002/014312 pamphlet-   [Patent Document 9] WO2002/046173 pamphlet-   [Patent Document 10] WO2003/095438 pamphlet-   [Patent Document 11] WO2004/052869 pamphlet-   [Patent Document 12] WO2004/072031 pamphlet-   [Patent Document 13] WO2004/072066 pamphlet-   [Patent Document 14] WO2005/103021 pamphlet-   [Patent Document 15] WO2006/016174 pamphlet-   [Patent Document 16] WO2006/016178 pamphlet-   [Patent Document 17] WO2006/016194 pamphlet-   [Patent Document 18] WO2006/059163 pamphlet-   [Patent Document 19] U.S. Pat. No. 6,911,545-   [Patent Document 20] WO2007/026761 pamphlet-   [Patent Document 21] WO2008/012227 pamphlet

Non-Patent Document

-   [Non-Patent Document 1] Diabetes 45, 223-241 (1996)-   [Non-Patent Document 2] Diabetes 41, 792-806 (1992)-   [Non-Patent Document 3] FASEB J.10, 1213-1218 (1996)

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

It is an object of the present invention to provide compounds having anexcellent GK activating effect or an excellent hypoglycemic effect andto make use of the compounds for the treatment or prevention ofdiabetes, obesity, and the like.

Means for Solving the Problems

The present inventors have conducted extensive studies to solve theabove problems and found that, among acrylamide compounds having a3,4-difluorocyclopentyl group at 3-position thereof, compounds havingspecific stereo structures have excellent GK activating and hypoglycemiceffects. Thus, the present invention has been completed.

Accordingly, the present invention relates to the following:

(1) A compound represented by the general formula (1) or apharmaceutically acceptable salt thereof:

(wherein R¹ and R² are each independently a hydrogen atom, a halogenatom, an amino group, a hydroxyl group, a hydroxyamino group, a nitrogroup, a cyano group, a sulfamoyl group, a C₁ to C₆ alkyl group, a C₁ toC₆ alkoxy group, a C₁ to C₆ alkylsulfanyl group, a C₁ to C₆alkylsulfinyl group, a C₁ to C₆ alkylsulfonyl group, or a C₁ to C₆alkoxy-C₁ to C₆ alkylsulfonyl group, and A is a substituted orunsubstituted heteroaryl group).

(2) The compound according to (1) or a pharmaceutically acceptable saltthereof, wherein R¹ and R² are each independently a hydrogen atom, ahalogen atom, or a C₁ to C₆ alkylsulfonyl group.

(3) The compound according to (1) or a pharmaceutically acceptable saltthereof, wherein R¹ is a hydrogen atom or a halogen atom, and R² is a C₁to C₆ alkylsulfonyl group.

(4) The compound according to (1) or a pharmaceutically acceptable saltthereof, wherein R¹ is a hydrogen atom and R² is a C₁ to C₆alkylsulfonyl group.

(5) The compound according to (1) or a pharmaceutically acceptable saltthereof, wherein R¹ is a hydrogen atom, and R² is a cyclopropylsulfonylgroup.

(6) The compound according to (1) or a pharmaceutically acceptable saltthereof, wherein R¹ is a hydrogen atom, and R² is a methylsulfonylgroup.

(7) The compound according to any of (1) to (6) or a pharmaceuticallyacceptable salt thereof, wherein the compound is represented by thegeneral formula (1a):

(wherein R¹, R², and A are as defined in (1)).

(8) The compound according to any of (1) to (6) or a pharmaceuticallyacceptable salt thereof, wherein the compound is represented by thegeneral formula (1b):

(wherein R¹, R², and A are as defined in (1)).

(9) The compound according to any of (1) to (8) or a pharmaceuticallyacceptable salt thereof, wherein A is an unsubstituted heteroaryl groupor a heteroaryl group that is mono-substituted with a halogen atom, a C₁to C₆ alkyl group optionally substituted with a halogen atom or ahydroxyl group, a C₁ to C₆ alkoxy group optionally substituted with ahalogen atom or a hydroxyl group, a nitro group, a cyano group, or agroup represented by the formula of —(O)_(p) (CH₂)_(m)C(O)OR³ (whereinR³ is a hydrogen atom or a C₁ to C₆ alkyl group, m is an integer of 0 to2, and p is 0 or 1).

(10) The compound according to any of (1) to (8) or a pharmaceuticallyacceptable salt thereof, wherein A is a heteroaryl group that ismono-substituted with a halogen atom, a C₁ to C₆ alkyl group, or a C₁ toC₆ hydroxyalkyl group.

(11) The compound according to any of (1) to (8) or a pharmaceuticallyacceptable salt thereof, wherein A is a heteroaryl group that ismono-substituted with a C₁ to C₆ alkoxy group optionally substitutedwith a halogen atom or a hydroxyl group, or a C₁ to C₃ alkoxy-C₁ to C₃alkoxy group.12) The compound according to any of (1) to (8) or a pharmaceuticallyacceptable salt thereof, wherein A is a heteroaryl group that ismono-substituted with a C₁ to C₆ alkylsulfanyl group that is optionallysubstituted with a halogen atom or a hydroxyl group.

(13) The compound according to any of (9) to (12) or a pharmaceuticallyacceptable salt thereof, wherein A is an unsubstituted ormono-substituted five- or six-membered heteroaromatic ring, theheteroaromatic ring containing 1 to 3 heteroatoms selected from a sulfuratom, an oxygen atom, and a nitrogen atom, one of which is a nitrogenatom adjacent to a ring-connecting atom.

(14) The compound according to any of (9) to (12) or a pharmaceuticallyacceptable salt thereof, wherein A is an unsubstituted ormono-substituted fused heterocycle having a five- or six-memberedheteroaromatic ring, the heteroaromatic ring containing 1 to 3heteroatoms selected from a sulfur atom, an oxygen atom, and a nitrogenatom, one of the heteroatoms being a nitrogen atom adjacent to aring-connecting atom.

(15) The compound according to any of (9) to (12) or a pharmaceuticallyacceptable salt thereof, wherein A is an unsubstituted or substitutedheteroaromatic ring selected from the following rings:

(16) The compound according to (1), or a pharmaceutically acceptablesalt thereof, selected from the group consisting of(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-fluorothiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-N-(5-chlorothiazol-2-yl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(4-methylthiazol-2-yl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(5-methylthiazol-2-yl)acrylamide,(+)-(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(−)-(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(+)-(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(1,2-dihydroxyethyl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(−)-(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(1,2-dihydroxyethyl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-N-[4-tert-butylthiazol-2-yl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-{4-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]thiazol-2-yl}acrylamide,E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(2-hydroxyethyl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(N,N-dimethylsulfamoyl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(4-methylpiperazine-1-ylsulfonyl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(3-methyl-1,2,4-thiadiazol-5-yl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(3-ethyl-1,2,4-thiadiazol-5-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(pyridin-2-yl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-fluoropyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-N-(5-chloropyridin-2-yl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-[5-(methylthio)pyridin-2-yl]acrylamide,(E)-N-(5-cyclopropylpyridin-2-yl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(hydroxymethyl)pyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(N,N-dimethylsulfamoyl)pyridin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(pyrazin-2-yl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-methylpyrazin-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-ethylpyrazin-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-methoxypyrazin-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methylethoxyl)pyrazin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methoxyethoxyl)pyrazin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(3-methoxypropoxy)pyrazin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-ethoxyethoxyl)pyrazin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-{5-[2-(methylthio)ethoxy]pyrazin-2-yl}acrylamide,(E)-2-(4-(methylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-hydroxyethylthio)pyrazin-2-yl]acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-{5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyrazin-2-yl}acrylamide,(E)-3-[(1α,3α4α)-3,4-difluorocyclopentyl]-N-[5-(2-(hydroxyethoxy)pyrazin-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrazin-2-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrazin-2-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(2R)-1,2-dihydroxyethyl]pyrazin-2-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(2S)-1,2-dihydroxyethyl]pyrazin-2-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,diethyl5-{(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl-2-(4-(methylsulfonyl)phenyl)]acrylamide}pyrazin-2-ylphosphonate,diethyl(5-{(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl-2-(4-(methylsulfonyl)phenyl)]acrylamide}pyrazin-2-yl)methylphosphonate,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-methyl-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-ethyl-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(2-fluoroethyl)-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{1-[(2R)-2,3-dihydroxypropyl]-1H-pyrazol-3-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{1-[(2S)-2,3-dihydroxypropyl]-1H-pyrazol-3-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(isoxazol-3-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(6-methoxybenzo[d]thiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[6-(difluoromethoxy)benzo[d]thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methoxyethoxyl)thiazolo[5,4-b]pyridin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,and ethyl(E)-2-{2-[(R)-2-(4-(methylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide]thiazolo[5,4-b]pyridin-2-yloxy}acetate.(17) The compound according to (1), or a pharmaceutically acceptablesalt thereof, selected from the group consisting of(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-fluorothiazol-2-yl)acrylamide,(E)-N-(5-bromothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(4-methylthiazol-2-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-methylthiazol-2-yl)acrylamide,(+)-(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)thiazol-2-yl]acrylamide,(−)-(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)thiazol-2-yl]acrylamide,(E)-N-(4-tert-butylthiazol-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(4-methylpiperazin-1-ylsulfonyl)thiazol-2-yl]acrylamide,methyl3-{2-[(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide]thiazol-4-yl]propionate,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1,2,4-thiadiazol-5-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(3-methyl-1,2,4-thiadiazol-5-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(3-ethyl-1,2,4-thiadiazol-5-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(3-phenyl-1,2,4-thiadiazol-5-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(pyridin-2-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(methylthio)pyridin-2-yl]acrylamide,(E)-N-(5-cyclopropylpyridin-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(hydroxymethyl)pyridin-2-yl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(N,N-dimethylsulfamoyl)pyridin-2-yl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(pyrazin-2-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-methylpyrazin-2-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-ethylpyrazin-2-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-methoxypyrazin-2-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(methylthio)pyrazin-2-yl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methylethoxyl)pyrazin-2-yl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methoxyethoxyl)pyrazin-2-yl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(3-methoxypropoxy)pyrazin-2-yl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-ethoxyethoxyl)pyrazin-2-yl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[2-(methylthio)ethoxy]pyrazin-2-yl}acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyrazin-2-yl}acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-(hydroxyethoxy)pyrazin-2-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrazin-2-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrazin-2-yl}acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(2R)-1,2-dihydroxyethyl]pyrazin-2-yl}acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(2S)-1,2-dihydroxyethyl]pyrazin-2-yl}acrylamide,diethyl5-{(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide}pyrazin-2-ylphosphonate,diethyl(5-{(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide}pyrazin-2-ylmethylphosphonate,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-methyl-1H-pyrazol-3-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-ethyl-1H-pyrazol-3-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(2-hydroxyethyl)-1H-pyrazol-3-yl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-yl}acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-yl}acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{1-[(2R)-2,3-dihydroxypropyl]-1H-pyrazol-3-yl}acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-yl}acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(isoxazol-3-yl)acrylamide,(E)-N-(benzo[d]thiazol-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(6-methoxybenzo[d]thiazol-2-yl)acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[6-difluoromethoxy]benzo[d]thiazol-2-yl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(6-fluorobenzo[d]thiazol-2-yl)acrylamide,2-methylethyl2-{(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide}benzo[d]thiazol-6-carboxylicacid,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(thiazolo[5,4-b]pyridin-2-yl)acrylamide,(E)-N-(5-butoxythiazolo[5,4-b]pyridin-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide,(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methoxyethoxyl)thiazolo[5,4-b]pyridin-2-yl)acrylamide,and ethyl2-{2-[(R)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide]thiazolo[5,4-b]pyridin-5-yloxy}acetate.(18) The compound according to (1), or a pharmaceutically acceptablesalt thereof, selected from the group consisting of(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]-N-(thiazol-2-yl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]-N-(5-methylpyrazin-2-yl)acrylamide,and(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]-N-(1-methyl-1H-pyrazol-3-yl)acrylamide.(19) The compound according to (1), or a pharmaceutically acceptablesalt thereof, selected from the group consisting of(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]-N-(thiazol-2-yl)acrylamide,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]-N-(5-methylpyrazin-2-yl)acrylamide,and(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]-N-(1-methyl-1H-pyrazol-3-yl)acrylamide.

(20) A method for treating or preventing diabetes, comprisingadministering the compound according to any of (1) to (19) or apharmaceutically acceptable salt thereof.

(21) Use of a compound according to any of (1) to (19) or apharmaceutically acceptable salt thereof for manufacturing apharmaceutical for treatment or prevention of diabetes.

(22) A pharmaceutical composition, comprising the compound according toany of (1) to (19), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

(23) A compound represented by the general formula (2):

(wherein R¹ and R² are each independently a hydrogen atom, a halogenatom, an amino group, a hydroxyl group, a hydroxyamino group, a nitrogroup, a cyano group, a sulfamoyl group, a C₁ to C₆ alkyl group, a C₁ toC₆ alkoxy group, a C₁ to C₆ alkylsulfanyl group, a C₁ to C₆alkylsulfinyl group, a C₁ to C₆ alkylsulfonyl group, or a C₁ to C₆alkoxy-C₁ to C₆ alkylsulfonyl group).

(24) The compound according to (23), wherein R¹ is a hydrogen atom, andR² is a cyclopropylsulfonyl group.

(25) The compound according to (23), wherein R¹ is a hydrogen atom, andR² is a methylsulfonyl group.

Advantages of the Invention

According to the present invention, compounds having an excellent GKactivating or hypoglycemic effect and few side effects (such as Q-Tinterval prolongation (relating to hERG current suppression) andinsulin-induced hypoglycemia) are provided, and thereforepharmaceuticals excellent for the treatment or prevention of diabetes,obesity, and the like can be provided.

BEST MODE FOR CARRYING OUT THE INVENTION

The term “halogen atom” refers to a fluorine atom, a chlorine atom, abromine atom, or an iodine atom.

The term “C₁ to C₆ alkyl group” is a linear or branched alkyl grouphaving 1 to 6 carbon atoms or a cyclic alkyl group having 3 to 6 carbonatoms. Examples of the C₁ to C₆ alkyl group include a methyl group, anethyl group, a propyl group, an isopropyl group, a butyl group, anisobutyl group, a sec-butyl group, a tert-butyl group, a cyclopropylgroup, and a cyclobutyl group.

The term “C₁ to C₆ alkoxy group” is a linear or branched alkoxy grouphaving 1 to 6 carbon atoms or a cyclic alkoxy group having 3 to 6 carbonatoms. Examples of the C₁ to C₆ alkoxy group include a methoxy group, anethoxy group, a propoxy group, an isopropoxy group, a butoxy group, anisobutoxy group, a sec-butoxy group, a tert-butoxy group, a cyclopropoxygroup, and a cyclobutoxy group.

The term “C₁ to C₆ alkylsulfanyl group” is a linear or branchedalkylsulfanyl group having 1 to 6 carbon atoms or a cyclic alkylsulfanylgroup having 3 to 6 carbon atoms. Examples of the C₁ to C₆ alkylsulfanylgroup include a methylsulfanyl group, an ethylsulfanyl group, apropylsulfanyl group, an isopropylsulfanyl group, a butylsulfanyl group,an isobutylsulfanyl group, a sec-butylsulfanyl group, atert-butylsulfanyl group, a cyclopropylsulfanyl group, acyclobutylsulfanyl group, and a cyclopentylsulfanyl group.

The term “C₁ to C₆ alkylsulfinyl group” is a linear or branchedalkylsulfinyl group having 1 to 6 carbon atoms or a cyclic alkylsulfinylgroup having 3 to 6 carbon atoms. Examples of the C₁ to C₆ alkylsulfinylgroup include a methylsulfinyl group, an ethylsulfinyl group, apropylsulfinyl group, an isopropylsulfinyl group, a butylsulfinyl group,an isobutylsulfinyl group, a sec-butylsulfinyl group, atert-butylsulfinyl group, a cyclopropylsulfinyl group, acyclobutylsulfinyl group, and a cyclopentylsulfinyl group.

The term “C₁ to C₆ alkylsulfonyl group” is a linear or branchedalkylsulfonyl group having 1 to 6 carbon atoms or a cyclic alkylsulfonylgroup having 3 to 6 carbon atoms. Examples of the C₁ to C₆ alkylsulfonylgroup include a methylsulfonyl group, an ethylsulfonyl group, apropylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group,an isobutylsulfonyl group, a sec-butylsulfonyl group, atert-butylsulfonyl group, a cyclopropylsulfonyl group, acyclobutylsulfonyl group, and a cyclopentylsulfonyl group.

The term “C₁ to C₆ alkoxy-C₁ to C₆ alkylsulfonyl group” is a linear orbranched alkylsulfonyl group having 1 to 6 carbon atoms that issubstituted with a linear or branched alkoxy group having 1 to 6 carbonatoms or with a cyclic alkoxy group having 3 to 6 carbon atoms. Examplesthereof include a methoxymethylsulfonyl group, a methoxyethylsulfonylgroup, a methoxypropylsulfonyl group, an isopropoxymethylsulfonyl group,and a cyclopropoxy methylsulfonyl group.

The term “heteroaryl group” is a five- or six-membered heteroaromaticring containing 1 to 3 heteroatoms selected from a sulfur atom, anoxygen atom, and a nitrogen atom as the constituent atom of the ring,and the heteroaromatic ring may optionally form a fused ring with abenzene ring or a five- or six-membered heteroaromatic ring. Preferredexamples of the heteroaryl group include a group in which theheteroaromatic ring contains 1 to 3 heteroatoms selected from a sulfuratom, an oxygen atom, and a nitrogen atom and in which one of theheteroatoms is a nitrogen atom adjacent to a ring-connecting atom. Thering-connecting atom is an atom in the ring that is involved in the bondto the nitrogen atom in the amide group, and a carbon atom is preferredas the ring-connecting atom.

Preferred examples of the heteroaryl group include a thiazolyl group, athiadiazolyl group, a pyrazolyl group, a pyridyl group, a pyrazinylgroup, a pyrimidinyl group, a pyridazinyl group, an oxazolyl group, anisoxazolyl group, an imidazolyl group, a triazinyl group, abenzothiazolyl group, a benzoxazolyl group, a benzimidazolyl group, apyridothiazolyl group, and a quinolinyl group. More preferably, theheteroaryl group is a thiazolyl group, a pyrazolyl group, a pyrazinylgroup, a pyridyl group, a thiazolo[5,4-b]pyridinyl group, a thiadiazolylgroup, or a pyridothiazolyl group.

Preferably, the “substituted or unsubstituted heteroaryl group” in A isan unsubstituted or mono-substituted heteroaryl group. Examples of thesubstituent include: halogen atoms; C₁ to C₆ alkyl groups optionallysubstituted with a halogen atom or a hydroxyl group (such as a methylgroup, a tert-butyl group, a cyclopropyl group, a fluoroethyl group, adifluoromethyl group, and a 1,2-dihydroxyethyl group); C₁ to C₆ alkoxygroups optionally substituted with a halogen atom or a hydroxyl group;C₁ to C₃ alkoxy-C₁ to C₃ alkoxy groups; C₁ to C₃ alkoxycarbonyl-C₁ to C₃alkoxy groups; C₁ to C₃ alkoxycarbonyl-C₁ to C₆ alkylsulfanyl groups; C₁to C₆ alkylsulfanyl groups; C₁ to C₆ aminoalkylsulfanyl group optionallysubstituted with a C₁ to C₃ alkyl group; C₁ to C₆ alkylsulfanyl-C₁ to C₆alkoxy groups; aryl groups (such as a phenyl group), heteroaryl groups;aliphatic heterocyclyl groups optionally substituted with a C₁ to C₆alkyl group (such as a morpholino group and a dioxolyl group); aliphaticheterocyclylcarbonyl groups; aliphatic heterocyclylsulfonyl groups;aliphatic heterocyclyl-C₁ to C₃ alkyl groups; aliphatic heterocyclyl-C₁to C₃ alkoxy group; aliphatic heterocyclyloxy-C₁ to C₃ alkoxy groups;aminosulfonyl groups optionally substituted with a C₁ to C₃ alkyl group;C₁ to C₆ hydroxyalkylsulfanyl groups; a nitro group; a cyano group;groups represented by the formula of

—(O)_(p)(CH₂)_(m)C(O)OR³

(wherein R³ is a hydrogen atom, a C₁ to C₆ alkyl group, or a C₁ to C₃alkoxy-C₁ to C₃ alkyl group, m is an integer of 0 to 2, and p is 0 or1); and groups represented by the formula of

—(CH₂)_(m)P(O)R⁴R⁵

(wherein R⁴ and R⁵ are each independently a hydroxyl group, a C₁ to C₃alkyl group, or a C₁ to C₃ alkoxy group, and m is an integer of 0 to 2).

Examples of the pharmaceutically acceptable salt include salts ofinorganic and organic acids such as hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,maleic acid, acetic acid, succinic acid, and tartaric acid.

Specific examples of the compound according to the present inventioninclude the following compounds and pharmaceutically acceptable saltsthereof.

-   (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-fluorothiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-N-(5-chlorothiazol-2-yl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(4-methylthiazol-2-yl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(5-methylthiazol-2-yl)acrylamide,    (+)-(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (−)-(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (+)-(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(1,2-dihydroxyethyl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (−)-(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(1,2-dihydroxyethyl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-N-[4-tert-butylthiazol-2-yl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-{4-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]thiazol-2-yl}acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(2-hydroxyethyl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(N,N-dimethylsulfamoyl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(4-methylpiperazine-1-ylsulfonyl)thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(3-methyl-1,2,4-thiadiazol-5-yl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(3-ethyl-1,2,4-thiadiazol-5-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(pyridin-2-yl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-fluoropyridin-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-N-(5-chloropyridin-2-yl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-[5-(methylthio)pyridin-2-yl]acrylamide,    (E)-N-(5-cyclopropylpyridin-2-yl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(hydroxymethyl)pyridin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(N,N-dimethylsulfamoyl)pyridin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-(pyrazin-2-yl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-methylpyrazin-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-ethylpyrazin-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-methoxypyrazin-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methylethoxyl)pyrazin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methoxyethoxyl)pyrazin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(3-methoxypropoxy)pyrazin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-ethoxyethoxy)pyrazin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-{5-[2-(methylthio)ethoxy]pyrazin-2-yl}acrylamide,    (E)-2-(4-(methylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-hydroxyethylthio)pyrazin-2-yl]acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-{5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyrazin-2-yl}acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-(hydroxyethoxy)pyrazin-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrazin-2-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrazin-2-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(2R)-1,2-dihydroxyethyl]pyrazin-2-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(2S)-1,2-dihydroxyethyl]pyrazin-2-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,    diethyl    5-{(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl-2-(4-(methylsulfonyl)phenyl)]acrylamide}pyrazin-2-ylphosphonate,    diethyl(5-{(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl-2-(4-(methylsulfonyl)phenyl)]acrylamide}pyrazin-2-yl)methylphosphonate,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-methyl-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-ethyl-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(2-fluoroethyl)-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-(4-(methylsulfonyl)phenyl)-N-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{1-[(2R)-2,3-dihydroxypropyl]-1H-pyrazol-3-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{1-[(2S)-2,3-dihydroxypropyl]-1H-pyrazol-3-yl}-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(isoxazol-3-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(6-methoxybenzo[d]thiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[6-(difluoromethoxy)benzo[d]thiazol-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methoxyethoxyl)thiazolo[5,4-b]pyridin-2-yl]-2-(4-(methylsulfonyl)phenyl)acrylamide,    ethyl    (E)-2-{2-[(R)-2-(4-(methylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide]thiazolo[5,4-b]pyridin-2-yloxy}acetate,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-fluorothiazol-2-yl)acrylamide,    (E)-N-(5-bromothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(4-methylthiazol-2-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-methylthiazol-2-yl)acrylamide,    (+)-(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)thiazol-2-yl]acrylamide,    (−)-(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)thiazol-2-yl]acrylamide,    (E)-N-(4-tert-butylthiazol-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(4-methylpiperazin-1-ylsulfonyl)thiazol-2-yl]acrylamide,    methyl    3-(2-[(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide]thiazol-4-yl]propionate,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1,2,4-thiadiazol-5-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(3-methyl-1,2,4-thiadiazol-5-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(3-ethyl-1,2,4-thiadiazol-5-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(3-phenyl-1,2,4-thiadiazol-5-yl)    acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(pyridin-2-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(methylthio)pyridin-2-yl]acrylamide,    (E)-N-(5-cyclopropylpyridin-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(hydroxymethyl)pyridin-2-yl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(N,N-dimethylsulfamoyl)pyridin-2-yl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(pyrazin-2-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-methylpyrazin-2-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-ethylpyrazin-2-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-methoxypyrazin-2-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(methylthio)pyrazin-2-yl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methylethoxyl)pyrazin-2-yl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methoxyethoxyl)pyrazin-2-yl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(3-methoxypropoxy)pyrazin-2-yl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-ethoxyethoxyl)pyrazin-2-yl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[2-(methylthio)ethoxy]pyrazin-2-yl}acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyrazin-2-yl}acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-(hydroxyethoxy)pyrazin-2-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrazin-2-yl}acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrazin-2-yl}acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(2R)-1,2-dihydroxyethyl]pyrazin-2-yl}acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{5-[(2S)-1,2-dihydroxyethyl]pyrazin-2-yl}acrylamide,    diethyl    5-{(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide}pyrazin-2-yl    phosphonate,    diethyl(5-{(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide}pyrazin-2-yl    methylphosphonate,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-methyl-1H-pyrazol-3-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-ethyl-1H-pyrazol-3-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(2-hydroxyethyl)-1H-pyrazol-3-yl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-yl}acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-yl}acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-{1-[(2R)-2,3-dihydroxypropyl]-1H-pyrazol-3-yl}acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-yl}acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(isoxazol-3-yl)acrylamide,    (E)-N-(benzo[d]thiazol-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(6-methoxybenzo[d]thiazol-2-yl)    acrylamide, (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,    4α)-3,4-difluorocyclopentyl]-N-[6-difluoromethoxy]benzo[d]thiazol-2-yl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(6-fluorobenzo[d]thiazol-2-yl)acrylamide,    2-methylethyl    2-{(E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide}benzo[d]thiazol-6-carboxylic    acid,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(thiazolo[5,4-b]pyridin-2-yl)acrylamide,    (E)-N-(5-butoxythiazolo[5,4-b]pyridin-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide,    (E)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(2-methoxyethoxyl)thiazolo[5,4-b]pyridin-2-yl)acrylamide,    ethyl    2-{2-[(R)-2-(4-(cyclopropylsulfonyl)phenyl)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide]thiazolo[5,4-b]pyridin-5-yloxy}acetate,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]-N-(thiazol-2-yl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]-N-(5-methylpyrazin-2-yl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]-N-(1-methyl-1H-pyrazol-3-yl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]-N-(thiazol-2-yl)acrylamide,    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]-N-(5-methylpyrazin-2-yl)acrylamide,    and    (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]-N-(1-methyl-1H-pyrazol-3-yl)acrylamide.

The compound represented by the general formula (1) of the presentinvention can be produced by, for example, the following productionprocess with the compound represented by the general formula (2) as anintermediate:

(wherein R¹, R², and A are as defined above).

In this process, the compound represented by the general formula (2) isreacted with a heteroarylamine in the presence of a suitable reagent toproduce the compound represented by the general formula (1).

This reaction may be performed using an appropriate method such as amethod using a general condensation agent, the active ester method, themixed anhydride method, the acid halide method, or the carbodiimidemethod. Examples of the reagent used in the above reaction includethionyl chloride, oxalyl chloride, N,N′-dicyclohexylcarbodiimide,N,N′-diisopropylcarbodiimide, 1-methyl-2-bromopyridinium iodide,N,N′-carbonyldiimidazole, diphenylphosphoryl chloride,diphenylphosphoryl azide, N,N′-disuccinimidyl carbonate,N,N′-disuccinimidyl oxalate,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, ethylchloroformate, isobutyl chloroformate,benzotriazo-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate,and N-bromosuccinimide/triphenylphosphine. In this process, a base and acondensation aid may be used together with the above reagent. Any basecan be used in this process, so long as it is not involved in thereaction. The reaction can be performed in the presence of such a base.Examples of the base include: alkali metal alkoxides such as sodiummethoxide and sodium ethoxide; alkali metal hydrides such as sodiumhydride and potassium hydride; alkali metal organic bases such asn-butyllithium, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide;tertiary organic bases such as triethylamine, diisopropylethylamine,pyridine, N-methylmorpholine, imidazole, N-methylpyrrolidine,N-methylpiperidine, 1,5-diazabicyclo[4.3.0]non-5-ene, and1,8-diazabicyclo[5.4.0]undec-7-ene; and inorganic bases such aspotassium carbonate and sodium hydrogen carbonate. Examples of thecondensation aid include N-hydroxybenzotriazole hydrate,N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboxyimide,3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, and pentafluorophenol.Any solvent can be used as the reaction solvent, so long as it is notinvolved in the reaction. Preferred examples of such a solvent include:hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene,toluene, and xylene; halogenated hydrocarbon solvents such asdichloromethane, 1,2-dichloroethane, chloroform, and carbontetrachloride; ether solvents such as diethyl ether, tetrahydrofuran,and 1,4-dioxane; and aprotic polar solvents such as acetonitrile,propionitrile, nitromethane, nitroethane, N,N-dimethylformamide,N-methylpiperidone, sulfolane, and dimethyl sulfoxide. The reactiontypically proceeds smoothly at −78° C. to 200° C.

Furthermore, the compounds represented by the formulae (1) and (2) ofthe present invention can also be produced based on the followingproduction steps.

(wherein R⁶ represents an optionally substituted alkoxy group or anoptionally substituted amino group, R⁷ represents a boric acidderivative, a halogen atom, or a trifluoromethanesulfonyloxy group, andX represents a halogen atom; R¹ and R² are as defined above)

(First Step)

This step is for producing an acrylic acid derivative (4) by reactingthe compound represented by the formula (3) with a glyoxylaldehyde inthe presence of a base. Examples of the base used in this reactioninclude alkali metal amides such as lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassiumbis(trimethylsilyl)amide, metal hydrides such as lithium hydride, sodiumhydride, and potassium hydride, potassium carbonate, tert-butoxypotassium, and n-butyllithium. In this reaction, lithiumbis(trimethylsilyl)amide is preferred.

Any solvent can be used as the solvent used in this reaction, as long asit is not involved in the reaction. Examples of such a solvent includehydrocarbon solvents such as pentane, hexane, cyclohexane, benzene,toluene, and xylene, halogenated hydrocarbon solvents such asdichloromethane, 1,2-dichloroethane, chloroform, and carbontetrachloride, and ether solvents such as diethyl ether,tetrahydrofuran, and 1,4-dioxane. The reaction proceeds smoothly at −80°C. to 80° C.

(Second Step)

This step is for producing a 3-(3,4-difluorocyclopentyl)-2-halogenoacrylic acid derivative by halogenating the 3-(3,4-difluorocyclopentyl)acrylic acid derivative represented by the formula (4) obtained in theabove first step with molecular halogen, and then reacting with thebase.

Examples of the base used in this reaction include carbonic acid saltssuch as sodium carbonate, potassium carbonate, calcium carbonate, cesiumcarbonate, and barium carbonate, or organic bases such as triethylamine,diisopropylethylamine, N,N,N,N-tetramethylethylenediamine,diazabicyclo[5.4.0]-7-undecene, diazabicyclo[4.3.0]-5-nonene,phosphazene bases, and pentaisopropylguanidine. However, in thisreaction, triethylamine is preferred.

Any solvent can be used as the solvent used in this reaction, as long asit is not involved in the reaction. Examples of such a solvent includehydrocarbon solvents such as pentane, hexane, cyclohexane, benzene,toluene, and xylene, halogenated hydrocarbon solvents such asdichloromethane, 1,2-dichloroethane, chloroform, and carbontetrachloride, and ether solvents such as diethyl ether,tetrahydrofuran, and 1,4-dioxane. The reaction proceeds smoothly at −80°C. to 80° C.

(Third Step)

This step is for producing a 3-(3,4-difluorocyclopentyl)-2-(substitutedphenyl)acrylic acid derivative by reacting a compound represented by theformula (6) with the 3-(3,4-difluorocyclopentyl)-2-halogeno acrylic acidderivative represented by the formula (5) obtained in the above secondstep in the presence of a catalyst and a base.

In the formula, if R⁷ is a halogen atom or a trifluoromethanesulfonyloxygroup, for example, boric acid, pinacolato diboron or the like can bereacted to convert the compound into a boric acid derivative for use inthe presence of a palladium complex, such as1,1-bis(diphenylphosphino)ferrocene-palladium (II) dichloride, and anacetic acid salt, such as potassium acetate. The thus-obtained boricacid derivative is used after isolated and purified, or is prepared inthe reaction system. As the catalyst used in this reaction,tetrakis(triphenylphosphine)palladium, palladium acetate, or a palladiumcomplex such as 1,1-bis(diphenylphosphino)ferrocene-palladium (II)dichloride, can be used.

As the base used in this reaction, a carbonic acid salt such as sodiumcarbonate, potassium carbonate, calcium carbonate, cesium carbonate, andbarium carbonate, or an acetic acid salt such as potassium acetate andsodium acetate, can be used.

Any solvent can be used as the reaction solvent, so long as it is notinvolved in the reaction. Examples of such a solvent include:hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene,toluene, and xylene; halogenated hydrocarbon solvents such asdichloromethane, 1,2-dichloroethane, chloroform, and carbontetrachloride; ether solvents such as diethyl ether, tetrahydrofuran,and 1,4-dioxane; aprotic polar solvents such as acetonitrile,propionitrile, nitromethane, nitroethane, N,N-dimethylformamide, anddimethyl sulfoxide; alcohol solvents such as methanol, ethanol,1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol,2-methyl-2-propanol, and benzyl alcohol; and water. One kind of solvent,or two or three kinds of solvents in combination, may be used. Thereaction proceeds smoothly at −80° C. to 150° C.

One embodiment of the present invention relates to a pharmaceuticalcontaining, as an active ingredient, the compound represented by theformula (1) or a pharmaceutically acceptable salt thereof. Thepharmaceuticals of the present invention have a GK activating effect ora hypoglycemic effect and therefore is useful for the treatment orprevention of type I diabetes, type II diabetes, hyperlipemia (hyper LDLcholesterolemia, hypertriglyceridemia, and hypo HDL cholesterolemia),obesity, insulin resistance, impaired glucose tolerance, metabolicsyndrome, and the like.

The pharmaceutical of the present invention may be administered orallyor parenterally, for example, intrarectally, subcutaneously,intravenously, intramuscularly, or percutaneously.

The compound of the present invention or a pharmaceutically acceptablesalt thereof may be used as pharmaceuticals in any form (for example, asolid composition, a liquid composition, or other type of composition).An optimal form is selected in accordance with need. The pharmaceuticalof the present invention can be produced by adding a pharmaceuticallyacceptable carrier to the compound of the present invention. Morespecifically, commonly used additives such as excipient, extender,binder, disintegrator, coating, sugar-coating agent, pH modifier, andsolubilizing agent and an aqueous or non-aqueous solvent are added tothe compound of the present invention, and the mixture can be formedinto various forms such as tablets, pills, capsules, granules, powders,powdered drugs, liquid formulations, emulsions, suspensions, andinjections by any commonly used formulation method.

The dose of the compound of the present invention or a pharmaceuticallyacceptable salt thereof depends on the type of disease, the condition,weight, age, and sex of a patient, the route of administration, and thelike. The oral dose for an adult is preferably about 0.01 to about 1000mg/kg body weight/day, and more preferably about 0.5 to about 200 mg/kgbody weight/day. This amount may be administered in a single dose or individed doses throughout the day.

If necessary, the compound of the present invention or apharmaceutically acceptable salt thereof may be used together with oneor more compounds other than GK activators. For example, the compound ofthe present invention or a pharmaceutically acceptable salt thereof maybe used in combination with one or more of anti-obesity agents andantidiabetic (or hypoglycemic) agents including sulfonylureas,biguanides, glucagon antagonists, α-glucosidase inhibitors, insulinsecretion promoters, insulin sensitizers, and the like.

Examples of the sulfonylureas include glyburide, glimepiride, glipiride,glipizide, chlorpropamide, gliclazide, glisoxepide, acetohexamide,glibornuride, tolbutamide, tolazamide, carbutamide, gliquidone,glyhexamide, phenbutamide, and tolcyclamide. Examples of the biguanidesinclude metformin, phenformin, and buformin. Examples of the glucagonantagonists include peptide and non-peptide glucagon antagonists.Examples of the α-glucosidase inhibitors include acarbose, voglibose,and miglitol. Examples of the insulin sensitizers include troglitazone,rosiglitazone, pioglitazone, and ciglitazone. Examples of theanti-obesity agents include sibutramine and orlistat. The compound ofthe present invention or a pharmaceutically acceptable salt thereof maybe administered simultaneously, sequentially or separately with otherantidiabetic, hypoglycemic, and anti-obesity agents.

Example 13-[(1α,3α,4α)-3,4-Difluorocyclopentyl]-2-[4-(methylthio)phenyl]acrylicacid ethyl ester

(1α,3α,4α)-(3,4-Difluorocyclopentyl)methyltriphenylphosphonium iodide(2.67 g) was suspended in tetrahydrofuran (10 mL). Lithiumbis(trimethylsilyl)amide (a 1 mol/L tetrahydrofuran solution, 5.30 mL)was added to the suspension at −40° C. in an argon atmosphere, and themixture was stirred at −40° C. for 2 hours. Subsequently, a solution of2-[(4-methylthio)phenyl]oxoacetic acid ethyl ester (1.12 g) intetrahydrofuran (3.70 mL) was added dropwise to the reaction mixturecooled to −40° C., and the resultant mixture was stirred at −40° C. for2 hours and further stirred at room temperature for 18 hours. Water (10mL) was added to the reaction mixture, and the pH of the mixture wasadjusted to 2 with 3 mol/L hydrochloric acid. Tetrahydrofuran wasevaporated under reduced pressure, and the residue was extracted withethyl acetate (20 mL×2). The ethyl acetate extracts were combined,washed with saturated brine (10 mL), dried over anhydrous sodiumsulfate, filtrated, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent; hexane:ethylacetate=4:1) to give3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylthio)phenyl]acrylicacid ethyl ester (1.54 g).

¹H NMR (400 MHz, CDCl₃) δ 1.27 (t, J=7.3 Hz, 3H), 1.30 (t, J=7.3 Hz,3H), 1.84-2.19 (m, 6H), 2.28-2.42 (m, 2H), 2.49 (s, 3H), 2.50 (s, 3H),2.55-2.69 (m, 1H), 3.17-3.31 (m, 1H), 4.21 (q, J=7.3 Hz, 2H), 4.27 (q,J=7.3 Hz, 2H), 4.68-5.04 (m, 4H), 6.13 (d, J=9.8 Hz, 1H), 7.00 (d,J=10.4 Hz, 1H), 7.03-7.08 (m, 2H), 7.22-7.25 (m, 6H).

MS (ESI⁺) m/z: 327 (MH⁺).

Example 23-[(1α,3α,4α)-3,4-Difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]acrylicacid ethyl ester

3-[(1α,3α,4α)-3,4-Difluorocyclopentyl]-2-[4-(methylthio)phenyl]acrylicacid ethyl ester (3.00 g) was dissolved in dichloromethane (31 mL).m-Chloroperoxybenzoic acid (5.37 g) was added to the prepared solutioncooled in an ice bath, and the mixture was stirred for 0.5 hours whilecooled in the ice bath and further stirred at room temperature for 1.5hours. Insoluble materials in the reaction mixture were removed byfiltration, and the filtrate was diluted with dichloromethane (42 mL).The obtained dichloromethane solution was washed with a 10% aqueoussodium sulfite solution (20 mL×2), a saturated aqueous sodium hydrogencarbonate solution (20 mL×2), and saturated brine (20 mL), dried overanhydrous sodium sulfate, filtrated, and concentrated under reducedpressure to give3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]acrylicacid ethyl ester (3.41 g).

¹H NMR (400 MHz, CDCl₃) δ 1.30 (t, J=7.3 Hz, 3H), 1.31 (t, J=7.3 Hz,3H), 1.86-2.20 (m, 6H), 2.30-2.56 (m, 3H), 3.06 (s, 3H), 3.10 (s, 3H),3.35-3.48 (m, 1H), 4.24 (q, J=7.3 Hz, 2H), 4.29 (q, J=7.3 Hz, 2H),4.69-5.10 (m, 4H), 6.29 (d, J=9.8 Hz, 1H), 7.09 (d, J=10.4 Hz, 1H),7.33-7.38 (m, 2H), 7.48-7.53 (m, 2H), 7.89-7.93 (m, 2H), 7.93-7.97 (m,2H).

MS (EI) m/z: 358 (M⁺).

Example 3(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]acrylicacid methyl ester

3-[(1α,3α,4α)-3,4-Difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]acrylicacid ethyl ester (5.00 g) was suspended in methanol (26 mL). A sodiummethoxide solution prepared from 460 mg of sodium and 20 mL of methanolwas added dropwise to the obtained suspension at room temperature, andthe resultant mixture was stirred at room temperature for 3 hours.Methanol was evaporated under reduced pressure, and the resultantresidue was collected by filtration and washed with methanol (50 mL) togive(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]acrylicacid methyl ester (3.98 g).

¹H NMR (400 MHz, CDCl₃) δ 1.87-2.20 (m, 4H), 2.43-2.58 (m, 1H), 3.10 (s,3H), 3.78 (s, 3H), 4.69-4.95 (m, 2H), 7.12 (d, J=11.0 Hz, 1H), 7.34 (d,J=7.9 Hz, 2H), 7.96 (d, J=7.9 Hz, 2H).

MS (EI) m/z: 344 (M⁺).

Example 4(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]acrylicacid

A mixed solution of concentrated sulfuric acid (6.89 mL), acetic acid(37.1 mL), and water (22.5 mL) was added to(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]acrylicacid methyl ester (3.95 g), and the mixture was stirred under heating at103° C. (internal temperature) for 3 hours. After allowed to cool, thereaction mixture was evaporated under reduced pressure. Water (37 mL)was added to the residue, and the precipitate was collected byfiltration and washed with water (100 mL). The collected precipitate wasdissolved in a saturated aqueous sodium hydrogen carbonate solution andextracted with dichloromethane (15 mL×2). Concentrated hydrochloric acidwas added to the aqueous layer, while cooled in an ice bath, to make itacidic. The resultant precipitate was collected by filtration and washedwith water (100 mL) to give(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]acrylicacid (3.26 g).

¹H NMR (400 MHz, CDCl₃) δ 1.88-2.21 (m, 4H), 2.47-2.62 (m, 1H), 3.09 (s,3H), 4.73-4.97 (m, 2H), 7.24 (d, J=10.4 Hz, 1H), 7.34-7.39 (m, 2H),7.94-7.99 (m, 2H).

MS (EI) m/z: 330 (M⁺).

Example 5(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]-N-(thiazol-2-yl)acrylamide(Compound 1A of the Present Invention)

Thionyl chloride (3.43 mL) was added to(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]acrylicacid (343 mg), and the mixture was heated to reflux for 45 minutes.After the mixture was cooled to room temperature, thionyl chloride wasremoved by evaporation. Toluene (3 mL×3) was added to the mixture, andthe resultant mixture was evaporated under reduced pressure. A solutionof 2-aminothiazole (104 mg) in pyridine (1.37 mL) was added to theresultant residue in a salted ice bath, and the mixture was stirred atroom temperature for 1 hour. The reaction mixture was diluted with ethylacetate (30 mL) and washed sequentially with 1 mol/L hydrochloric acid(30 mL×2), a saturated aqueous sodium hydrogen carbonate solution (30mL×2) and saturated brine (30 mL), dried over anhydrous sodium sulfate,and filtrated, and the solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography(eluent; chloroform:methanol=50:1), and the obtained compound was washedwith diethyl ether to give(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]-N-(thiazol-2-yl)acrylamide(154 mg).

MS (ESI⁺) m/z: 413 (MH⁺).

HRMS (ESI⁺) for C₁₈H₁₉F₂N₂O₃S₂(MH⁺): calcd., 413.08051; found,413.08048.

¹H NMR (400 MHz, CDCl₃) δ 1.82-2.01 (m, 2H), 2.07-2.25 (m, 2H),2.48-2.60 (m, 1H), 3.25 (s, 3H), 4.84-5.08 (m, 2H), 7.83 (d, J=10.4 Hz,1H), 7.21 (brs, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.51 (d, J=3.1 Hz, 1H),7.94 (d, J=8.6 Hz, 2H), 12.4 (brs, 1H).

Example 6

Compounds 2A to 62A of the present invention were produced according tothe same procedure as in Example 5.

In the following Tables, the optical rotations of the compounds 7A, 8A,40A, 41A, 53A, and 54A of the present invention were measured usingmethanol as a solvent, and the optical rotations of the compounds 51Aand 52A of the present invention were measured using dichloromethane.The optical rotations of the rest of the compounds of the presentinvention were measured using chloroform.

TABLE 1 Compound Optical No. Structure (A) 1H NMR (400 MHz) MS (m/z)rotation 2A

(CDCl3) δ 1.93-2.15 (m, 4H), 2.38-2.48 (m, 1H), 3.17 (s, 3H), 4.75-4.80(m, 1H), 4.88-4.93 (m, 1H), 6.99 (d, J = 2.5 Hz, 1 H), 7.25 (d, J = 9.2Hz, 1H), 7.45 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H), 8.13 (s,1H). (ESI+) 431.1 (MH+) 3A

(DMSO-d6) δ 1.80-2.00 (m, 2H), 2.04-2.25 (m, 2H), 2.47-2.70 (m, 1H),3.25 (s, 3H), 4.78-5.12 (m, 2H), 6.88 (d, J = 10.4 Hz, 1H), 7.47 (d, J =8.6 Hz, 2H), 7.56 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 12.7 (s, 1H).(ESI+) 447.1 (MH+) 4A

(CDCl3) δ 1.71-2.18 (m, 4H), 2.30 (s, 3H), 2.35-2.48 (m, 1H), 3.18 (s,3H), 4.71-4.95 (m, 2H), 6.57 (d, J = 1.2 Hz, 1H), 7.27 (d, J = 10.4 Hz,1H), 7.43-7.48 (m, 2H), 8.05-8.10 (m, 2H), 8.36 (brs, 1H). (ESI+) 427.1(MH+) 5A

(CDCl3) δ 1.92-2.19 (m, 4H), 2.35-2.48 (m, 1H), 2.41 (d, J = 1.2 Hz,3H), 3.17 (s, 3H), 4.72-4.95 (m, 2H), 7.04 (d, J = 1.2 Hz, 1H), 7.25 (d,J = 11.0 Hz, 1H), 7.44-7.47 (m, 2H), 8.04-8.10 (m, 2H), 8.30 (brs, 1H).(ESI+) 427.1 (MH+) 6A

(CDCl3) δ 1.43 (s, 3H), 1.47 (s, 3H), 1.96-2.20 (m, 4H), 2.37-2.49 (m,1H), 3.19 (s, 3H), 3.93 (dd, J = 7.9, 6.7 Hz, 1H), 4.27 (dd, J = 7.9,6.7 Hz, 1H), 4.74-4.80 (m, 1H), 4.87-4.93 (m, 1H), 5.07 (t, J = 6.7 Hz,1H), 6.94 (s, 1H), 7.26 (d, J = 11.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 2H),8.09 (d, J = 8.6 Hz, 2H), 8.39 (s, 1H). (ESI+) 513.1 (MH+) (+)

TABLE 2 7A

(CDCl3) δ 1.43 (s, 3H), 1.47 (s, 3H), 1.96-2.20 (m, 4H), 2.37-2.49 (m,1H), 3.19 (s, 3H), 3.93 (dd, J = 7.9, 6.7 Hz, 1H), 4.27 (dd, J = 7.9,6.7 Hz, 1H), 4.74-4.80 (m, 1H), 4.87-4.93 (m, 1H), 5.07 (t, J = 6.7 Hz,1H), 6.94 (s, 1H), 7.26 (d, J = 11.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 2H),8.09 (d, J = 8.6 Hz, 2H), 8.40 (s, 1H). (ESI+) 513.1 (MH+) (−) 8A

(CDCl3) δ 1.93-2.19 (m, 4H), 2.36 (brs, 1H), 2.40-2.52 (m, 1H),3.07-3.14 (m, 1H), 3.18 (s, 3H), 3.69-3.84 (m, 2H), 4.67-4.74 (m, 1H),4.74-4.82 (m, 1H), 4.86-4.96 (m, 1H), 6.91 (s, 1H), 7.24 (d, J = 11.2Hz, 1 H), 7.46 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 2H), 8.75 (s, 1H).(ESI+) 437.1 (MH+) (+) 9A

(CDCl3) δ 1.93-2.19 (m, 4H), 2.36 (brs, 1H), 2.40-2.52 (m, 1H),3.07-3.14 (m, 1H), 3,18 (s, 3H) 3.69-3.84 (m, 2H), 4.67-4.74 (m, 1H),4.74-4.82 (m, 1H), 4.86-4.96 (m, 1H), 6.91 (s, 1H), 7.24 (d, J = 11.2Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 2H), 8.75 (s,1H). (ESI+) 437.1 (MH+) (−) 10A

(CDCl3) δ 1.26 (s, 9H), 1.90-2.19 (m, 4H), 2.37-2.52 (m, 1H), 3.18 (s,3H), 4.71-4.96 (m, 2H), 6.58 (s, 1H), 7.19 (d, J = 10.4 Hz, 1H),7.44-7.49 (m, 2H), 8.05-8.11 (m, 2H), 8.46 (brs, 1H). (ESI+) 469.1 (MH+)11A

(CDCl3) δ 1.42-1.85 (m, 6H), 1.90-2.19 (m, 4H), 2.36-2.49 (m, 1H), 2.91(t, J = 6.7 Hz, 2H), 3.18 (s, 3H), 3.41-3.50 (m, 1H), 3.65 (td, J = 9.8,6.7 Hz, 1H), 3.71-3.81 (m, 1H), 3.97 (td, J = 9.8, 6.7 Hz, 1H), 4.57 (t,J = 4.3 Hz, 1H), 4.72-4.95 (m, 2H), 6.71 (s, 1H), 7.25 (d, J = 9.8 Hz,1H), 7.44-7.48 (m, 2H), 8.08 (d, J = 7.9 Hz, 2H), 8.43 (brs, 1H). (ESI+)541.2 (MH+)

TABLE 3 12A

(CDCl3) δ 1.91-2.19 (m, 4H), 2.36-2.50 (m, 1H), 2.55 (brs, 1H), 2.85 (t,J = 5.5 Hz, 2H), 3.18 (s, 3H), 3.85 (q, J = 5.5 Hz, 2H), 4.72-4.96 (m,2H), 6.69 (s, 1H), 7.25 (d, J = 11.6 Hz, 1H), 7.44-7.49 (m, 2H),8.06-8.11 (m, 2H), 8.48 (brs, 1H). (ESI+) 457.1 (MH+) 13A

(CDCl3) δ 1.93-2.19 (m, 4H), 2.41-2.54 (m, 1H), 2.79 (s, 6H), 3.18 (s,3H), 4.74-4.97 (m, 2H), 7.31 (d, J = 10.4 Hz, 1H), 7.45-7.49 (m, 2H),7.83 (s, 1H), 8.07-8.12 (m, 2H), 8.67 (brs, 1H). (ESI+) 520.1 (MH+) 14A

(DMSO-d6) δ 1.82-1.99 (m, 2H), 2.10-2.20 (m, 2H), 2.39-2.41 (m, 4H),2.51-2.65 (m, 1H), 2.90-3.00 (m, 4H), 3.26 (s, 3H), 4.86-4.95 (m, 1H),5.00-5.07 (m, 1H), 6.95 (d, J = 10.4 Hz, 1H), 7.46 (d, J = 7.9 Hz, 2H),7.95 (d, J = 8.6 Hz, 2H), 8.02 (s, 1H), 13.1 (s, 1H). (ESI+) 575.1 (MH+)15A

(CDCl3) δ 1.93-2.22 (m, 4H), 2.42-2.56 (m, 1H), 3.19 (s, 3H), 4.75-4.97(m, 2H), 7.32-7.38 (m, 1H), 7.46-7.50 (m, 2H), 8.11 (dd, J = 8.6, 1.8Hz, 2H), 8.29 (d, J = 1.2 Hz, 1H), 8.91-9.05 (m, 1H). (ESI+) 414.1 (MH+)16A

(CDCl3) δ 1.92-2.20 (m, 4H), 2.39-2.56 (m, 1H), 2.51 (s, 3H), 3.18 (s,3H), 4.73-4.97 (m, 2H), 7.34 (d, J = 10.4 Hz, 1H), 7.44-7.50 (m, 2H),8.08-8.12 (m, 2H), 8.76 (brs, 1H). (ESI+) 428.1 (MH+) 17A

(CDCl3) δ 1.33 (t, J = 7.9 Hz, 3H), 1.94-2.20 (m, 4H), 2.42-2.55 (m,1H), 2.85 (q, J = 7.9 Hz, 2H), 3.20 (s, 3H), 4.75-4.98 (m, 2H), 7.35 (d,J = 10.4 Hz, 1H), 7.45-7.51 (m, 2H), 8.09-8.14 (m, 2H), 8.76 (brs, 1H).(ESI+) 442.1 (MH+) 18A

(CDCl3) δ 1.93-2.18 (m, 4H), 2.42-2.52 (m, 1H), 3.18 (s, 3H), 4.01 (s,3H), 4.74-4.83 (m, 1H), 4.88-4.96 (m, 1H), 7.32 (d, J = 10.4 Hz, 1H),7.46 (d, J = 7.9 Hz, 2H), 8.10 (d, J = 8.6 Hz, 2H), 8.74 (s, 1H). (ESI+)444.1 (MH+)

TABLE 4 19A

(CDCl3) δ 1.90-2.20 (m, 4H), 2.37-2.46 (m, 1H), 3.16 (s, 3H), 4.70-4.82(m, 1H), 4.88-4.93 (m, 1H), 7.06 (dd, J = 6.7, 4.9 Hz, 1H), 7.13 (d, J =10.4 Hz, 1H), 7.48 (d, J = 7.9 Hz, 2H), 7.64 (s, 1H), 7.74 (t, J = 7.9Hz, 1H), 8.06 (d, J = 8.6 Hz, 2H), 8.21 (d, J = 3.7 Hz, 1H), 8.30 (d, J= 7.9 Hz, 1H). (ESI+) 407.2 (MH+) 20A

(CDCl3) δ 1.91-2.19 (m, 4H), 2.35-2.50 (m, 1H), 3.16 (s, 3H), 4.72-4.95(m, 2H), 7.13 (d, J = 10.4 Hz, 1H), 7.43-7.51 (m, 3H), 7.64 (brs, 1H),8.04-8.10 (m, 3H), 8.32 (dd, J = 9.2, 4.3 Hz, 1H). (ESI+) 425.1 (MH+)21A

(CDCl3) δ 1.92-2.20 (m, 4H), 2.36-2.50 (m, 1H), 3.16 (s, 3H), 4.72-4.95(m, 2H), 7.13 (d, J = 11.0 Hz, 1H), 7.44-7.51 (m, 2H), 7.64 (brs, 1H),7.70 (dd, J = 8.6, 2.4 Hz, 1H), 8.04-8.10 (m, 2H), 8.16 (d, J = 1.8 Hz,1H), 8.29 (d, J = 9.8 Hz, 1H). (ESI+) 441.1 (MH+) 22A

(CDCl3) δ 1.92-2.19 (m, 4H), 2.35-2.47 (m, 1H), 2.47 (s, 3H), 3.16 (s,3H), 4.72-4.95 (m, 2H), 7.12 (d, J = 10.4 Hz, 1H), 7.45-7.50 (m, 2H),7.62 (brs, 1H), 7.66 (dd, J = 8.6, 2.4 Hz, 1H), 8.04-8.09 (m, 8.13 (d, J= 1.8 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H). (ESI+) 453.1 (MH+) 23A

(CDCl3) δ 0.61-0.71 (m, 2H), 0.94-1.04 (m, 2H), 1.77-1.90 (m, 1H),1.91-2.19 (m, 4H), 2.33-2.48 (m, 1H), 3.16 (s, 3H), 4.70-4.95 (m, 2H),7.11 (d, J = 10.4 Hz, 1H), 7.35 (dd, J = 8.6, 2.4 Hz, 1H), 7.44-7.50 (m,2H), 7.59 (brs, 1H), 8.01 (d, J = 2.4 Hz, 1H), 8.03-8.08 (m, 2H), 8.18(d, J = 8.6 Hz, 1H). (ESI+) 447.2 (MH+) 24A

(CDCl3) δ 1.70 (t, J = 5.8 Hz, 1H), 1.90-2.30 (m, 4H), 2.40-2.47 (m,1H), 3.16 (s, 3H), 4.69 (d, J = 5.8 Hz, 2H), 4.74-4.80 (m, 1H),4.87-4.93 (m, 1H), 7.13 (d, J = 10.4 Hz, 1 H), 7.48 (d, J = 8.6 Hz, 1H),7.68 (s, 1H), 7.76 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 8.06 (d, J = 8.6 Hz,2H), 8.20 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 8.6 Hz, 1H). (ESI+) 437.1(MH+)

TABLE 5 25A

(CDCl3) δ 1.90-2.17 (m, 4H), 2.40-2.50 (m, 1H), 2.73 (s, 6H), 3.17 (s,3H), 4.75-4.81 (m, 1H), 4.90-4.95 (m, 1H), 7.17 (d, J = 10.4 Hz, 1 H),7.49 (d, J = 8.0 Hz, 2H), 7.87 (s, 1H), 8.06-8.10 (m, 3H), 1.47 (d, J =9.8 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H). (ESI+) 514.1 (MH+) 26A

(CDCl3) δ 1.95-2.14 (m, 4H), 2.39-2.50 (m, 1H), 3.16 (s, 3H), 4.75-4.95(m, 2H), 7.18 (d, J = 10.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.57 (brs,1H), 8.08 (d, J = 8.0 Hz, 2H), 8.19 (d, J = 1.8 Hz, 1H), 8.37 (d, J =2.5 Hz, 1H), 9.63 (d, J = 1.2 Hz, 1H). (ESI+) 408.1 (MH+) 27A

(CDCl3) δ 1.94-2.18 (m, 4H), 2.37-2.50 (m, 1H), 2.53 (s, 3H), 3.16 (s,3H), 4.73-4.94 (m, 1H), 7.16 d, J = 10.4 Hz, 1H), 7.49 (d, J = 8.6 Hz,2H), 7.50 (brs, 1H), 8.05 (d, J = 1.2 Hz, 2H), 8.08 (d, J = 8.7 Hz, 2H),9.49 (d, J = 1.2 Hz, 1H). (ESI+) 422.1 (MH+) 28A

(CDCl3) δ 1.31 (t, J = 7.3 Hz, 3H), 1.93-2.20 (m, 4H), 2.37-2.51 (m,1H), 2.82 (q, J = 7.3 Hz, 2H), 3.16 (s, 3H), 4.71-4.96 (m, 2H), 7.16 (d,J = 11.0 Hz, 1H), 7.46-7.51 (m, 2H), 7.52 (brs, 1H), 8.04-8.10 (m, 3H),9.51 (d, J = 1.2 Hz, 1H). (ESI+) 436.2 (MH+) 29A

(CDCl3) δ 1.92-2.20 (m, 4H), 2.37-2.48 (m, 1H), 3.15 (s, 3H), 4.00 (s,3H), 4.74-4.80 (m, 1H), 4.89-4.93 (m, 1H), 7.15 (d, J = 10.4 Hz, 1 H),7.42 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 1.8 Hz, 1H), 8.07(d, J = 8.6 Hz, 2H), 9.11 (d, J = 1.8 Hz, 1H). (ESI+) 438.1 (MH+) 30A

(CDCl3) δ 1.35 (d, J = 6.1 Hz, 6H), 1.98-2.15 (m, 4H), 2.36-2.47 (m,1H), 3.16 (s, 3H), 4.74-4.79 (m, 1H), 4.87-4.92 (m, 1H), 5.26 (sep, J =6.1 Hz, 1H), 7.15 (d, J = 10.4 Hz, 1H), 7.38 (s, 1H), 7.48 (d, J = 8.6Hz, 2H), 7.77 (d, J = 1.2 Hz, 1H), 8.07 (d, J = 8.6 Hz, 2H), 9.08 (d, J= 1.2 Hz, 1H). (ESI+) 466.2 (MH+)

TABLE 6 31A

(CDCl3) δ 1.93-2.18 (m, 4H), 2.36-2.48 (m, 1H), 3.15 (s, 3H), 3.43 (s,3H), 3.73-3.76 (m, 2H), 4.48-4.50 (m, 2H), 4.74-4.93 (m, 2H), 7.15 (d, J= 11.4 Hz, 1H), 7.42 (brs, 1H), 7.48 (dt, J = 8.6, 1.8 Hz, 2H), 7.91 (d,J = 1.2 Hz, 1H), 8.08 (dt, J = 8.6, 1.8 Hz, 2H), 9.09 (d, J = 1.8 Hz,1H), (ESI+) 482.2 (MH+) 32A

(CDCl3) δ 1.92-2.19 (m, 6H), 2.35-2.48 (m, 1H), 3.16 (s, 3H), 3.35 (s,3H), 3.53 (t, J = 6.7 Hz, 2H), 4.40 (t, J = 6.7 Hz, 2H), 4.71-4.95 (m,2H), 7.15 (d, J = 11.0 Hz, 1H), 7.41 (brs, 1H), 7.45-7.51 (m, 2H), 7.83(d, J = 1.8 Hz, 1H), 8.05-8.10 (m, 2H), 9.09 (d, J = 1.2 Hz, 1H). (ESI+)496.2 (MH+) 33A

(CDCl3) δ 1.23 (t, J = 7.3 Hz, 3H), 1.92-2.19 (m, 4H), 2.35-2.48 (m,1H), 3.15 (s, 3H), 3.58 (q, J = 7.3 Hz, 2H), 3.75-3.81 (m, 2H),4.44-4.51 (m, 2H), 4.72-4.94 (m, 2H), 7.15 (d, J = 10.4 Hz, 1H), 7.41(brs, 1H), 7.46-7.50 (m, 2H), 7.90 (d, J = 1.2 Hz, 1H), 8.05-8.09 (m,2H), 9.08 (d, J = 1.2 Hz, 1H). (ESI+) 496.2 (MH+) 34A

(CDCl3) δ 1.94-2.17 (m, 4H), 2.20 (s, 3H), 2.37-2.48 (m, 1H), 2.88 (t, J= 6.7 Hz, 2H), 3.16 (s, 3H), 4.51 (t, J = 6.7 Hz, 2H), 4.73-4.81 (m,1H), 4.86-4.94 (m, 1H), 7.15 (d, J = 10.4 Hz, 1 H), 7.42 (s, 1H), 7.48(d, J = 8.6 Hz, 2H), 7.86 (d, J = 1.2 Hz, 1H), 8.07 (d, J = 8.0 Hz, 2H),9.09 (d, J = 1.2 Hz, 1H). (ESI+) 498.1 (MH+) 35A

(CDCl3) δ 1.92-2.20 (m, 4H), 2.37-2.51 (m, 1H), 3.07 (t, J = 5.5 Hz,1H), 3.16 (s, 3H), 3.36 (t, J = 5.5 Hz, 2H), 3.92 (q, J = 5.5 Hz, 2H),4.72-4.96 (m, 2H), 7.16 (d, J = 10.4 Hz, 1H), 7.44-7.52 (m, 3H), 8.08(d, J = 7.9 Hz, 2H), 8.15 (d, J = 1.8 Hz, 1H), 9.40 (d, J = 1.2 Hz, 1H).(ESI+) 484.1 (MH+)

TABLE 7 36A

(CDCl3) δ 1.51-1.62 (m, 4H), 1.70-1.83 (m, 2H), 2.00-2.13 (m, 4H),2.37-2.47 (m, 1H), 3.16 (s, 3H), 3.49-3.53 (m, 1H), 3.78-3.82 (m, 1H),3.82-3.91 (m, 1H), 4.03-4.09 (m, 1H), 4.45-4.56 (m, 1H), 4.68 (t, J =3.7 Hz, 1H), 4.70-4.80 (m, 1H), 4.87-4.92 (m, 1H), 7.15 (d, J = 10.4 Hz,1H), 7.42 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 1.8 Hz, 1H),8.07 (d, J = 8.6 Hz, 2H), 9.09 (d, J = 1.8 Hz, 1H). (ESI+) 552.2 (MH+)37A

(DMSO-d6) δ 1.85-2.00 (m, 2H), 2.05-2.25 (m, 2H), 2.52-2.56 (m, 1H),3.24 (s, 3H), 3.70 (dd, J = 5.5 Hz, 4.9 Hz, 2H), 4.28 (t J = 4.9 Hz,2H), 4.85 (t, J = 5.5 Hz, 1H), 4.83-4.95 (m, 1H), 4.96-5.06 (m, 1H),6.70 (d, J = 10.4 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.6Hz, 2H), 8.24 (d, J = 1.8 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H), 10.6 (s,1H). (ESI+) 468.1 (MH+) 38A

(CDCl3) δ 1.49 (s, 3H), 1.52 (s, 3H), 1.92-2.21 (m, 4H), 2.38-2.52 (m,1H), 3.16 (s, 3H), 4.01 (dd, J = 8.6, 6.1 Hz, 1H), 4.45 (dd, J = 8.6,8.7 Hz, 1H), 4.73-4.96 (m, 2H), 5.21 (t, J = 6.7 Hz, 1H), 7.18 (d, J =10.4 Hz, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.61 (brs, 1H), 8.08 (d, J = 7.9Hz, 2H), 8.38 (d, J = 1.2 Hz, 1H), 9.53 (d, J = 1.2 Hz, 1H). (ESI+)508.2 (MH+) (−) 39A

(CDCl3) δ 1.49 (s, 3H), 1.51 (s, 3H), 1.92-2.21 (m, 1H), 2.38-2.52 (m,1H), 3.16 (s, 3H), 4.01 (dd, J = 8.6, 6.7 Hz, 1H), 4.45 (dd, J = 8.6,6.7 Hz, 1H), 1.73-4.97 (m, 2H), 5.21 (t, J = 6.7 Hz, 1H), 7.18 (d, J =10.4 Hz, 1H), 7.46-7.51 (m, 2H), 7.60 (brs, 1H), 8.06-8.10 (m, 2H), 8.38(s, 1H), 9.53 (d, J = 1.2 Hz, 1H). (ESI+) 508.2 (MH+) (+) 40A

(CD3OD) δ 1.85-2.05 (m, 2H), 2.08-2.28 (m, 2H), 2.56-2.70 (m, 1H), 3.16(s, 3H), 3.74 (dd, J = 11.6, 5.5 Hz, 1H), 3.85 (dd, J = 11.6, 4.9 Hz,1H), 4.73-4.97 (m, 3H), 6.85 (d, J = 10.4 Hz, 1H), 7.53-7.58 (m, 2H),8.00-8.05 (m, 2H), 8.48 (d, J = 1.2 Hz, 1H), 9.30 (d, J = 1.8 Hz, 1H).(ESI+) 468.1 (MH+) (−)

TABLE 8 41A

(CD3OD) δ 1.86-2.06 (m, 2H), 2.09-2.29 (m, 2H), 2.56-2.71 (m, 1H), 3.16(s, 3H), 3.74 (dd, J = 11.6, 6.1 Hz, 1H), 3.85 (dd, J = 11.6, 4.9 Hz,1H), 4.74-5.01 (m, 3H), 6.86 (d, J = 10.4 Hz, 1H), 7.54-7.58 (m, 2H),8.00-8.06 (m, 2H), 8.48 (d, J = 1.2 Hz, 1H), 9.30 (d, J = 1.8 Hz, 1H).(ESI+) 468.1 (MH+) (+) 42A

(CDCl3) δ 1.36 (t, J = 7.3 Hz, 6H), 1.93-2.22 (m, 4H), 2.39-2.53 (m,1H), 3.17 (s, 3H), 4.15-4.33 (m, 4H), 4.74-4.97 (m, 2H), 7.21 (d, J =10.4 Hz, 1H), 7.45-7.51 (m, 2H), 7.74 (brs, 1H), 8.06-8.12 (m, 2H),8.71-8.73 (m, 1H), 9.78 (d, J = 1.2 Hz, 1H). (ESI+) 544.2 (MH+) 43A

(CDCl3) δ 1.85 (t, J = 7.3 Hz, 6H), 1.98-2.17 (m, 4H), 2.39-2.50 (m,1H), 3.16 (s, 3H), 3.39 (d, J = 21.4 Hz, 2H), 4.06-4.13 (m, 4H),4.75-4.80 (m, 1H), 4.88-4.94 (m, 1H), 7.18 (d, J = 10.4 Hz, 1H), 7.49(d, J = 8.0 Hz, 2H), 7.57 (s, 1H), 8.08 (d, J = 8.0 Hz, 2H), 8.23 (t, J= 2.4 Hz, 1H), 9.54 (s, 1H). (ESI+) 558.2 (MH+) 44A

(CDCl3) δ 1.91-2.14 (m, 4H), 2.32-2.43 (m, 1H), 3.15 (s, 3H), 3.76 (s,3H), 4.71-4.92 (m, 2H), 6.76 (d, J = 2.5 Hz, 1H), 7.13 (d, J = 10.4 Hz,1H), 7.26 (d, J = 3.7 Hz, 1H), 7.44 (brs, 1H), 7.45 (dt, J = 8.6, 1.8Hz, 2H), 8.03 (dt, J = 8.6, 1.8 Hz, 2H). (ESI+) 410.1 (MH+) 45A

(CDCl3) δ 1.41 (t, J = 7.3 Hz, 3H), 1.88-2.18 (m, 4H), 2.30-2.45 (m,1H), 3.16 (s, 3H), 4.01 (q, J = 7.3 Hz, 2H), 4.69-4.94 (m, 2H), 6.76 (d,J = 1.8 Hz, 1H), 7.12 (d, J = 10.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H),7.43-7.50 (m, 3H), 8.04 (d, J = 8.6 Hz, 1H). (ESI+) 424.2 (MH+) 46A

(CDCl3) δ 1.93-2.17 (m, 4H), 2.35-2.46 (m, 1H), 3.16 (s, 3H), 4.72-4.92(m, 2H), 7.05 (d, J = 3.0 Hz, 1H), 7.10 (brs, 1H), 7.15 (d, J = 10.4 Hz,1H), 7.46 (dt, J = 8.0, 1.8 Hz, 21H), 7.71 (d, J = 2.9 Hz, 1H), 8.06(dt, J = 8.6, 1.8 Hz, 2H). (ESI+) 446.1 (MH+)

TABLE 9 47A

(CDCl3) δ 1.93-2.15 (m, 4H), 2.34-2.42 (m, 1H), 3.19 (s, 3H), 4.21 (t, J= 4.9 Hz, 1H), 4.28 (t, J = 4.9 Hz, 1H), 4.61 (t, J = 4.3 Hz, 1H), 4.72(t, J = 4.3 Hz, 1H), 4.71-4.78 (m, 1H), 4.85-4.90 (m, 1H), 6.81 (d, J =2.5 Hz, 1H), 7.12 (d, J = 10.4 Hz, 1 H), 7.37 (d, J = 2.5 Hz, 1H),7.45-7.47 (m, 1H), 7.46 (d, J = 8.0 Hz, 2H), 8.05 (d, J = 8.6 Hz, 2H).(ESI+) 442.1 (MH+) 48A

(CDCl3) δ 1.92-2.13 (m, 4H), 2.33-2.46 (m, 2H), 3.10 (s, 3H), 4.52 (q, J= 8.6 Hz, 2H), 4.72-4.92 (m, 2H), 6.94 (d, J = 2.5 Hz, 1H), 7.12 (d, J =10.4 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.46 (dt, J = 8.0, 1.8 Hz, 2H),7.51 (brs, 1H), 8.05 (dt, J = 9.0, 1.8 Hz, 2H). (ESI+) 478.1 (MH+) 49A

(CDCl3) δ 1.91-2.16 (m, 4H), 2.33-2.45 (m, 1H), 2.47 (t, J = 5.5 Hz,1H), 3.16 (s, 3H), 3.90 (q, J = 4.89 Hz, 2H), 4.10 (dd, J = 4.9, 6.1 Hz,2H), 4.72-4.93 (m, 2H), 6.80 (d, J = 2.5 Hz, 1H), 7.12 (d, J = 10.4 Hz,1H), 7.35 (d, J = 2.5 Hz, 1H), 7.45 (brs, 1H), 7.46 (dt, J = 8.6, 1.8Hz, 2H), 8.05 (dt, J = 8.0, 1.8 Hz, 2H). (ESI+) 440.1 (MH+) 50A

(CDCl3) δ 1.13 (s, 6H), 1.92-2.16 (m, 4H), 2.32-2.42 (m, 1H), 3.16 (s,3H), 3.28 (brs, 1H), 3.91 (s, 2H), 4.72-4.80 (m, 1H), 4.84-4.92 (m, 1H),6.82 (d, J = 2.4 Hz, 1 H), 7.12 (d, J = 11.0 Hz, 1 H), 7.32 (d, J = 2.4Hz, 1H), 7.46 (m, 2H), 8.06 (d, J = 7.9 Hz, 1H). (ESI+) 468.2 (MH+) 51A

(CDCl3) δ 1.32 (s, 3H), 1.36 (s, 3H), 1.96-2.11 (m, 2H), 2.33-2.44 (m,1H), 3.16 (s, 3H), 3.68 (dd, J = 8.6 Hz, 6.1 Hz, 1H), 4.01 (dd, J = 8.6Hz, 6.1 Hz, 1H), 4.06-4.08 (m, 2H), 4.32-4.38 (m, 1H), 4.71-4.79 (m,1H), 4.84-4.93 (m, 1H), 6.79 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 10.4 Hz,1H), 7.37 (d, J = 2.4 Hz, 1H), 7.44 (m, 3H), 8.05 (d, J = 6.1 Hz, 2H).(ESI+) 510.2 (MH+) (+)

TABLE 10 52A

(CDCl3) δ 1.32 (s, 3H), 1.36 (s, 3H), 1.91-2.16 (m, 4H), 2.31-2.46 (m,1H), 3.16 (s, 3H), 3.68 (dd, J = 8.6, 6.1 Hz, 1H), 4.01 (dd, J = 8.6,6.1 Hz, 1H), 4.05-4.09 (m, 2H), 4.31-4.40 (m, 1H), 4.70-4.94 (m, 2H),6.79 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 10.4 Hz, 1H), 7.37 (d, J = 1.8Hz, 1H), 7.42-7.49 (m, 3H), 8.02-8.07 (m, 2H). (ESI+) 397.1 (MH+) (−)53A

(CD3OD) δ 1.83-2.01 (m, 2H), 2.09-2.24 (m, 2H), 2.54-2.66 (m, 1H), 3.15(s, 3H), 3.45 (d, J = 5.5 Hz, 2H), 3.89-3.94 (m, 1H), 4.00 (dd, J =13.4, 7.4 Hz, 1H), 4.16 (dd, J = 13.4, 4.0 Hz, 1H), 4.73-4.95 (m, 2H),6.52 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 10.4 Hz, (ESI+) 470.2 (MH+) (+)1H), 7.51 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 8.6 Hz, 2H), 8.02 (d, J =8.6 Hz, 2H). 54A

(CD3OD) δ 1.81-2.01 (m, 2H), 2.08-2.26 (m, 2H), 2.52-2.67 (m, 1H), 3.15(s, 3H), 3.45 (d, J = 5.5 Hz, 2H), 3.88-3.95 (m, 1H), 4.00 (dd, J =14.1, 6.7 Hz, 1H), 4.16 (dd, J = 14.1, 4.3 Hz, 1H), 4.73-4.96 (m, 2H),6.52 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 10.4 Hz, (ESI+) (MH+) (−) 1H),7.49-7.55 (m, 3H), 7.99-8.05 (m, 2H). 55A

(CDCl3) δ 1.92-2.20 (m, 4H), 2.36-2.50 (m, 1H), 3.16 (s, 3H), 4.72-4.95(m, 2H), 7.14 (d, J = 1.8 Hz, 1H), 7.17 (d, J = 10.4 Hz, 1H), 7.44-7.49(m, 2H), 7.88-7.99 (m, 1H), 8.07 (d, J = 8.6 Hz, 2H), 8.31 (d, J = 1.8Hz, 1H). (ESI+) 397.1 (MH+) 56A

(DMSO-d6) δ 1.85-2.02 (m, 2H), 2.10-2.25 (m, 2H), 2.50-2.60 (m, 1H),3.26 (s, 3H), 4.87-4.93 (m, 1H), 5.00-5.05 (m, 1H), 6.92 (d, J = 10.4Hz, 1H), 7.03 (dd, J = 9.2, 2.4 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.56(d, J = 2.4 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 8.6 Hz, 2H),12.6 (s, 1H). (ESI+) 493.1 (MH+)

TABLE 11 57A

(DMSO-d6) δ 1.82-2.15 (m, 2H), 2.15-2.25 (m, 2H), 2.53-2.60 (m, 1H),3.26 (s, 3H), 4.85-4.95 (m, 1H), 5.00-5.07 (m, 1H), 6.96 (d, J = 10.4Hz, 1H), 7.21 (t, J = 86.2 Hz, 1H), 7.27 (dd, J = 8.6, 2.4 Hz, 1H), 7.50(d, J = 7.9 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.88 (s, 1H), 7.96 (d, J= 8.6 Hz, 2H), 12.7 (s, 1H). (ESI+) 529.1 (MH+) 58A

(DMSO-d6) δ 1.95-2.17 (m, 4H), 2.39-2.51 (m, 1H), 3.19 (s, 3H), 3.45 (s,3H), 3.77-3.79 (m, 2H), 4.54-4.67 (m, 2H), 4.75-4.95 (m, 2H), 6.88 (d, J= 3.6 Hz, 1H), 7.32 (d, J = 10.4 Hz, 1H), 7.49 (q, J = 3.6 Hz, 2H), 7.79(d, J = 9.2 Hz, 1H), 8.10 (d, J = 1.8 Hz, 2H), 8.41 (brs, 1H). (ESI+)538.1 (MH+) 59A

(CDCl3) δ 1.30 (t, J = 7.3 Hz, 3H), 1.91-2.20 (m, 4H), 2.38-2.52 (m,1H), 3.19 (s, 3H), 4.26 (q, J = 7.3 Hz, 2H), 4.74-4.99 (m, 2H), 4.96 (s,2H), 6.95 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 10.4 Hz, 1H), 7.49 (d, J =8.6 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 8.42(brs, 1H). (ESI+) 566.1 (MH+)

TABLE 12 No. Structure (A) 1H NMR (400 MHz) MS (m/z) 60A

(CDCl3) δ 1.16-1.22 (m, 2H), 1.46-1.50 (m, 2H), 1.98-2.20 (m, 4H),2.44-2.54 (m, 1H), 2.57-2.63 (m, 1H), 4.77-4.83 (m, 1H), 4.90-4.93 (m,1H), 7.36 (d, J = 11.0 Hz, 1H), 7.42-7.45 (m, 3H), 7.48 (d, J = 8.0 Hz,2H), 8.09 (d, J = 8.0 Hz, 2H), 8.11-8.14 (m, 2H), 8.88 (s, 1H). (ESI+)516.2 (MH+) 61A

(CDCl3) δ 1.41 (t, J = 7.3 Hz, 3H), 1.91-2.19 (m, 4H), 2.33-2.48 (m,1H), 3.15 (s, 3H), 4.04 (q, J = 7.3 Hz, 2H), 4.71-4.94 (m, 2H), 7.11 (d,J = 10.4 Hz, 1H), 7.27 (dd, J = 9.2, 3.1 Hz, 1H), 7.45-7.50 (m, 2H),7.54 (brs, 1H), 7.88 (d, J = 3.1 Hz, 1H), (ESI+) 451.2 (MH+) 8.03-8.08(m, 2H), 8.22 (d, J = 9.2 Hz, 1H). 62A

(CDCl3) δ 1.93-2.20 (m, 4H), 2.29-2.53 (m, 1H), 2.35 (s, 6H), 2.74 (t, J= 5.5 Hz, 2H), 3.19 (s, 3H), 4.48 (t, J = 5.5 Hz, 2H), 4.73-4.96 (m,2H), 6.86 (d, J = 9.2 Hz, 1H), 7.32 (d, J = 10.4 Hz, 1H), 7.49 (d, J =8.6 Hz, 2H), 7.78 (d, J = 9.2 Hz, 1H), 8.10 (d, J = 8.6 Hz, 2H). (ESI+)551.2 (MH+)

Example 7(E)-2-[4-(cyclopropylthio)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylicacid ethyl ester

(1α,3α,4α)-(3,4-Difluorocyclopentyl)methyltriphenylphosphonium iodide(60.9 g) was suspended in tetrahydrofuran (186 mL). Lithiumbis(trimethylsilyl)amide (a 1 mol/L tetrahydrofuran solution, 120 mL)was added to the suspension cooled in an ice bath, and the mixture wasstirred for 1 hour while cooled in the ice bath. A solution of[(4-cyclopropylthio)phenyl]oxoacetic acid ethyl ester (25.0 g) intetrahydrofuran (120 mL) was added dropwise to the reaction mixturecooled in an ice bath, and the resultant mixture was stirred for 1 hourwhile cooled in the ice bath and further stirred at room temperature for5 hours. Water (230 mL) was added to the reaction mixture, and the pH ofthe mixture was adjusted to 6 with 1 mol/L hydrochloric acid. Then,tetrahydrofuran was evaporated under reduced pressure, and the residuewas extracted with ethyl acetate (2×540 mL). The ethyl acetate extractswere combined, washed with saturated brine (180 mL), dried overanhydrous sodium sulfate, filtrated, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent; hexane:ethyl acetate=4:1) to give(E)-2-[4-(cyclopropylthio)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylicacid ethyl ester (12.2 g),(Z)-2-[4-(cyclopropylthio)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylicacid ethyl ester (7.71 g), and2-[4-(cyclopropylthio)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylicacid ethyl ester (14.5 g) (a mixture of E-form and Z-form). Of these,only the title compound was used in the next step.

MS (EI) m/z: 352 (M⁺).

HRMS (EI) for C₁₉H₂₂F₂N₂O₂S (M⁺): calcd., 352.1309; found, 352.1302.

¹H NMR (400 Mhz, CDCl₃) δ 0.69-0.73 (m, 2H), 1.04-1.11 (m, 2H), 1.28 (t,J=7.3 Hz, 3H), 1.89-2.03 (m, 2H), 2.06-2.21 (m, 3H), 2.58-2.69 (m, 1H),4.22 (q, J=7.3 Hz, 2H), 4.73-4.92 (m, 2H), 6.97 (d, J=10.4 Hz, 1H),7.03-7.37 (m, 2H).

Example 8(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylicacid ethyl ester

(E)-2-[4-(cyclopropylthio)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylicacid ethyl ester (8.81 g) was dissolved in dichloromethane (90 mL).m-Chloroperoxybenzoic acid (14.6 g) was added to the prepared solutioncooled in an ice bath, and the mixture was stirred for 1 hour whilecooled in the ice bath and further stirred at room temperature for 1hour. Insoluble materials in the reaction mixture were removed byfiltration, and the filtrate was diluted with dichloromethane (150 mL).The obtained dichloromethane solution was washed with a 10% aqueoussodium sulfite solution (2×35 mL), a saturated aqueous sodium hydrogencarbonate solution (2×35 mL), and water (35 mL), dried over anhydroussodium sulfate, filtrated, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent;hexane:ethyl acetate=1:1) to give(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylicacid ethyl ester (9.54 g).

MS (EI) m/z: 384 (M⁺).

HRMS (EI) for C₁₉H₂₂F₂N₂O₄S (M⁺): calcd, 384.1207; found, 384.1163.

¹H NMR (400 MHz, CDCl₃) δ 1.03-1.10 (m, 2H), 1.30 (t, J=7.3 Hz, 3H),1.34-1.41 (m, 2H), 1.91-2.17 (m, 4H), 2.47-2.58 (m, 2H), 4.24 (q, J=7.3Hz, 2H), 4.74-4.94 (m, 2H), 7.08 (d, J=10.4 Hz, 1H), 7.32-7.35 (m, 2H),7.87-7.92 (m, 2H).

Example 9(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylicacid

A mixed solution of concentrated sulfuric acid (15.0 mL), acetic acid(80.0 mL) and water (48.0 mL) was added to(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylicacid ethyl ester (9.54 g), and the mixture was stirred under heating at98° C. (internal temperature) for 6 hours. After allowed to cool, thereaction mixture was evaporated under reduced pressure. Water (80 mL)was added to the residue, and the precipitate was collected byfiltration and washed with water. The collected precipitate wasdissolved in a saturated aqueous sodium hydrogen carbonate solution (200mL) and washed with dichloromethane (50 mL×2). Concentrated hydrochloricacid was added to the aqueous layer, while cooled in an ice bath, tomake it acidic (pH=1), and the precipitate was collected by filtration.The collected precipitate was washed with water (100 mL) to give(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylicacid (7.79 g).

MS (EI) m/z: 356 (M⁺).

HRMS (EI) for C₁₇H₁₈F₂N₂O₄S (M⁺): calcd., 356.0894; found, 356.0870.

¹H NMR (400 MHz, CDCl₃) δ 1.05-1.10 (m, 2H), 1.30-1.41 (m, 2H),1.91-2.19 (m, 4H), 2.46-2.62 (m, 2H), 4.76-4.94 (m, 2H), 7.24 (d, J=11.0Hz, 1H), 7.34-7.36 (m, 2H), 7.91-7.93 (m, 2H).

Example 10(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(thiazol-2-yl)acrylamide(Compound 1B of the Present Invention)

Thionyl chloride (1.00 mL) was added to(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylicacid (108 mg), and the mixture was heated to reflux for 1.5 hours. Afterthe mixture was cooled to room temperature, thionyl chloride was removedby evaporation. Toluene (0.5 mL) was added to the mixture, and theresultant mixture was evaporated under reduced pressure. The obtainedresidue was dissolved in anhydrous tetrahydrofuran (0.4 mL). A solutionof 2-aminothiazole (30.3 mg) in pyridine (0.40 mL) was added to theprepared solution cooled in a salted ice bath, and the mixture wasstirred at room temperature for 1 hour. The reaction mixture was dilutedwith ethyl acetate (5 mL) and washed sequentially with 1 mol/Lhydrochloric acid (8 mL×2), a saturated aqueous sodium hydrogencarbonate solution (3 mL), and saturated brine (3 mL), dried overanhydrous sodium sulfate, and filtrated, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (eluent; chloroform:acetone=20:1), and theobtained compound was washed with diethyl ether to give(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(thiazol-2-yl)acrylamide(66.5 mg).

MS (ESI⁺) m/z: 439.1 (MH⁺).

HRMS (ESI⁺) for C₂₀H₂₁F₂N₂O₃S₂(MH⁺): calcd., 439.09616; found,439.09701.

¹H NMR (400 MHz, CDCl₃) δ 1.17 (ddd, J=13.4, 6.7, 2.5 Hz, 2H), 1.45(ddd, J=10.4, 6.1, 1.8 Hz, 2H), 1.93-2.17 (m, 4H), 2.37-2.17 (m, 1H),2.57 (tt, J=8.0, 4.9 Hz, 1H), 4.73-4.94 (m, 2H), 7.03 (d, J=3.7 Hz, 1H),7.27 (d, J=9.4 Hz, 1H), 7.41 (d J=3.67 Hz, 1H), 7.45 (dt, J=8.6, 1.8 Hz,2H), 8.03 (dt, J=8.5, 1.8 Hz, 2H), 8.51 (brs, 1H).

Example 11

Compounds 2B to 109B of the present invention were produced according tothe same procedure as in Example 10.

In the following Tables, the optical rotations of the compounds 6B and7B of the present invention were measured using methanol as a solvent,and the optical rotations of the rest of the compounds of the presentinvention were measured using chloroform.

TABLE 13 Compound Optical No. Structure (A) 1H NMR (400 MHz) MS (m/z)rotation 2B

(CDCl3) δ 1.13-1.20 (m, 2H), 1.42-1.48 (m, 2H), 1.89- 2.18 (m, 4H),2.34-2.48 (m, 1H), 2.52-2.61 (m, 1H), 4.72-4.94 (m, 2H), 7.00 (d, J =2.4 Hz, 1H), 7.26 (d, J = 10.4 Hz, 1H), 7.40-7.45 (m, 2H), 8.01-8.06 (m,2H), (ESI+) 457.1 (MH+) 8.15 (s, 1H). 3B

(CDCl3) δ 1.13-1.21 (m, 2H), 1.42-1.48 (m, 2H), 1.92-2.18 (m, 4H),2.36-2.48 (m, 1H), 2.52-2.61 (m, 1H), 4.72-4.95 (m, 2H), 7.26-7.30 (m,1H), 7.33 (s, 1H), 7.41- 7.45 (m, 2H), 8.01-8.06 (m, 2H), 8.42 (s, 1H).(ESI+) 517.0 (MH+) 4B

(CDCl3) δ 1.12-1.21 (m, 2H), 1.42-1.49 (m, 2H), 1.90-2.16 (m, 4H), 2.29(s, 3H), 2.37-2.47 (m, 1H), 2.53-2.62 (m, 1H), 4.69-4.94 (m, 2H), 6.57(d, J = 1.2 Hz, 1H), 7.27 (d, J = 10.4 Hz, 1H), 7.40-7.54 (m, 2H),7.99-8.05 (m, 2H), 8.40 (brs, 1H). (ESI+) (453.1 MH+) 5B

(DMSO-d6) δ 0.99-1.20 (m, 4H), 1.81-2.00 (m, 2H), 2.07-2.25 (m, 2H),2.33 (d, J = 1.2 Hz, 3H), 2.42-2.60 (m, 1H), 2.85-2.94 (m, 1H),4.83-5.09 (m, 2H), 6.80 (d, J = 10.4 Hz, 1H), 7.18 (d, J = 1.2 Hz, 1H),7.43-7.48 (m, 2H), 7.88-7.93 (m, 2H). (ESI+) 453.1 (MH+) 6B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.43 (s, 3H), 1.45-1.47 (m, 2H), 1.47 (s,3H), 1.93-2.16 (m, 4H), 2.36-2.47 (m, 1H), 2.55-2.62 (m, 1H), 3.93 (dd,J = 8.0, 6.7 Hz, 1H), 4.27 (dd, J = 8.0, 6.7 Hz, 1H), 4.73-4.81 (m, 1H),4.84-4.94 (m, 1H), 5.08 (t, J = 6.7 Hz, 1H), 6.94 (s, 1H), 7.27 (d, J =10.4 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 8.04 (d, J = 8.6 Hz, 2H), 8.45(s, 1H). (ESI+) 539.1 (MH+) (+)

TABLE 14  7B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.43 (s, 3H), 1.45-1.47 (m, 2H), 1.47 (s,3H), 1.93-2.16 (m, 4H), 2.36-2.47 (m, 1H), 2.55-2.62 (m, 1H), 3.93 (dd,J = 8.0, 6.7 Hz, 1H), 4.27 (dd, J = 8.0, 6.7 Hz, 1H), 4.73-4.81 (m, 1H),4.84-4.94 (m, 1H), 5.08 (t, J = 6.7 Hz, 1H), 6.94 (s, 1H), 7.27 (d, J =10.4 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 8.04 (d, J = 8.6 Hz, 2H), 8.45(s, 1H). (ESI+) 539.1 (MH+) (−)  8B

(CDCl3) δ 1.13-1.20 (m, 2H), 1.26 (s, 9H), 1.41-1.49 (m, 2H), 1.91-2.19(m, 4H), 2.37-2.50 (m, 1H), 2.53-2.63 (m, 1H), 4.71-4.95 (m, 2H), 6.59(s, 1H), 7.20 (d, J = 10.4 Hz, 1H), 7.42-7.47 (m, 2H), 8.01-8.06 (m,2H), 8.44 (brs, 1H). (ESI+) 495.2 (MH+)  9B

(CDCl3) δ 1.12-1.20 (m, 2H), 1.44-1.48 (m, 2H), 1.95-2.17 (m, 4H), 2.30(s, 3H), 2.43-2.54 (m, 6H), 3.07-3.16 (m, 4H), 4.74-4.97 (m, 2H), 7.30(d, J = 10.4 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.81 (s, 1H), 8.05 (d, J= 8.6 Hz, 2H). (ESI+) 601.1 (MH+) 10B

(CDCl3) δ 1.14-1.21 (m, 2H), 1.43-1.49 (m, 2H), 1.91-2.17 (m, 4H),2.35-2.49 (m, 1H), 2.54-2.68 (m, 3H), 2.94 (t, J = 7.6 Hz, 2H), 3.65 (s,3H), 4.71-4.94 (m, 2H), 6.63 (s, 1H), 7.23-7.26 (m, 1H), 7.41-7.45 (m,2H), 8.01-8.06 (m, 2H), 8.41 (s, 1H). (ESI+) 525.2 (MH+) 11B

(DMSO-d6) δ 1.01-1.19 (m, 4H), 1.82-2.26 (m, 4H), 2.42-2.69 (m, 1H),2.86-2.95 (m, 1H), 4.84-5.10 (m, 2H), 7.06 (d, J = 10.4 Hz, 1H), 7.50(d, J = 8.6 Hz, 2H), 7.90-7.94 (m, 2H), 8.51 (s, 1H), 13.3 (brs, 1H).(ESI+) 440.1 (MH+) 12B

(CDCl3) δ 1.12-1.22 (m, 2H), 1.41-1.50 (m, 2H), 1.93-2.18 (m, 4H),2.40-2.51 (m, 1H), 2.51 (s, 3H), 2.53-2.62 (m, 1H), 4.73-4.96 (m, 2H),7.34 (d, J = 10.4 Hz, 1H), 7.42-7.46 (m, 2H), 8.03-8.07 (m, 2H), 8.72(brs, 1H). (ESI+) 454.1 (MH+)

TABLE 15 13B

(CDCl3) δ 1.15-1.22 (m, 2H), 1.31 (t, J = 7.9 Hz, 3H), 1.43-1.50 (m,2H), 1.91-2.19 (m, 4H), 2.39-2.52 (m, 1H), 2.53-2.63 (m, 1H), 2.83 (q, J= 7.9 Hz, 2H), 4.72-4.96 (m, 2H), 7.34 (d, J = 10.4 Hz, 1H), 7.42-7.47(m, 2H), 8.03-8.08 (m, 2H), 8.73 (brs, 1H). (ESI+) 468.1 (MH+) 14B

(CDCl3) δ 1.16-1.22 (m, 2H), 1.46-1.50 (m, 2H), 1.98-2.20 (m, 4H),2.44-2.54 (m, 1H), 2.57-2.63 (m, 1H), 4.77-4.83 (m, 1H), 4.90-4.93 (m,1H), 7.36 (d, J = 11.0 Hz, 1H), 7.42-7.45 (m, 3H), 7.48 (d, J = 8.0 Hz,2H), 8.09 (d, J = 8.0 Hz, 2H), 8.11-8.14 (m, 2H), 8.88 (s, 1H) (ESI+)516.2 (MH+) 15B

(CDCl3) δ 1.09-1.18 (m, 2H), 1.40-1.47 (m, 2H), 1.92-2.18 (m, 4H),2.34-2.48 (m, 1H), 2.51-2.60 (m, 1H), 4.71-4.94 (m, 2H), 7.05 (ddd, J =8.3, 4.9, 1.2 Hz, 1H), 7.13 (d, J = 10.4 Hz, 1H), 7.43-7.48 (m, 2H),7.66 (s, 1H), 7.70-7.77 (m, 1H), 7.99-8.04 (m, 2H), (ESI+) 433.2 (MH+)8.21 (dd, J = 4.9, 1.2 Hz, 1H), 8.30 (d, J = 8.6 Hz, 1H). 16B

(CDCl3) δ 1.08-1.21 (m, 2H), 1.37-1.48 (m, 2H), 1.91-2.19 (m, 4H),2.35-2.49 (m, 1H), 2.47 (s, 3H), 2.50-2.60 (m, 1H), 4.69-4.96 (m, 2H),7.12 (d, J = 10.4 Hz, 1H), 7.43-7.47 (m, 2H), 7.64 (brs, 1H), 7.66 (dd,J = 8.6, 2.4 Hz, 1H), 7.98-8.04 (m, 2H), 8.13 (d, J = 2.4 Hz, 1H), 8.26(d, J = 8.6 Hz, 1H). (ESI+) 479.2 (MH+) 17B

(CDCl3) δ 0.60-0.73 (m, 2H), 0.93-1.04 (m, 2H), 1.08- 1.20 (m, 2H),1.39-1.47 (m, 2H), 1.79-1.90 (m, 1H), 1.91-2.18 (m, 4H), 2.33-2.47 (m,1H), 2.50-2.60 (m, 1H), 4.70-4.94 (m, 2H), 7.10 (d, J = 10.4 Hz, 1H),7.35 (dd, J = 8.6, 2.4 Hz, 1H), 7.42-7.46 (m, 2H), 7.62 (brs, 1H),7.98-8.03 (m, 3H), 8.18 (d, J = 8.6 Hz, 1H). (ESI+) 473.2 (MH+)

TABLE 16 18B

(DMSO-d6) δ 1.03-1.16 (m, 4H), 1.87-2.01 (m, 2H), 2.08-2.22 (m, 2H),2.50-2.57 (m, 1H), 2.86-2.93 (m, 1H), 4.47 (d, J = 5.5 Hz, 2H),4.85-5.05 (m, 2H), 5.24 (t, J = 5.8 Hz, 1H), 6.67 (d, J = 10.4 Hz, 1H),7.49 (d, J = 8.6 Hz, 2H), 7.71 (dd, J = 8.6, 2.4 Hz, (ESI+) 463.2 (MH+)1H), 7.91 (d, J = 8.6 Hz, 2H), 8.00 (d, J = 8.6 Hz, 1H), 8.27 (d, J =1.8 Hz, 1H), 10.5 (s, 1H). 19B

(CDCl3) δ 1.12-1.18 (m, 2H), 1.43-1.47 (m, 2H), 1.96-2.17 (m, 4H),2.41-2.50 (m, 1H), 2.53-2.59 (m, 1H), 2.73 (s, 6H), 4.75-4.96 (m, 2H),7.17 (d, J = 10.4 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.90 (s, 1H), 8.04(d, J = 8.6 Hz, 2H), 8.08 (dd, J = 8.6, 2.4 Hz, 1H), (ESI+) 540.1 (MH+)8.48 (d, J = 9.2 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H). 20B

(CDCl3) δ 1.11-1.18 (m, 2H), 1.42-1.47 (m, 2H), 1.93-2.20 (m, 4H),2.37-2.60 (m, 2H), 4.73-4.95 (m, 2H), 7.18 (d, J = 10.4 Hz, 1H),7.45-7.49 (m, 2H), 7.60 (s, 1H), 8.02-8.06 (m, 2H), 8.18-8.20 (m, 1H),8.37 (d, J = 2.4 Hz, 1H), 9.63 (d, J = 1.8 Hz, 1H). (ESI+) 434.2 (MH+)21B

(CDCl3) δ 1.14 (ddd, J = 14, 1, 6.1, 2.3 Hz, 2H), 1.45 (ddd, J = 11.0,6.1, 1.8 Hz, 2H), 1.94-2.18 (m, 4H), 2.39-2.50 (m, 1H), 2.53 (s, 3H),2.52-2.59 (m, 1H), 4.74-4.94 (m, 2H), 7.16 (d, J = 10.4 Hz, 1H), 7.46(d, J = 8.0 Hz, 2H), 7.52 (brs, 1H), 8.03 (d, J = (ESI+) 448.2 (MH+) 8.6Hz, 2H), 8.05 (s, 1H), 9.50 (d, J = 1.2 Hz, 1H). 22B

(CDCl3) δ 1.10-1.18 (m, 2H), 1.31 (t, J = 7.9 Hz, 3H), 1.41-1.47 (m,2H), 1.91-2.19 (m, 4H), 2.37-2.50 (m, 1H), 2.51-2.60 (m, 1H), 2.82 (q, J= 7.9 Hz, 2H), 4.71-4.95 (m, 2H), 7.16 (d, J = 10.4 Hz, 1H), 7.44-7.48(m, 2H), 7.54 (brs, 1H), 8.00-8.07 (ESI+) 462.2 (MH+) (m, 3H), 9.52 (d,J = 1.8 Hz, 1H).

TABLE 17 23B

(CDCl3) δ 1.11-1.17 (m, 2H), 1.42-1.46 (m, 2H), 1.94-2.17 (m, 4H),2.37-2.48 (m, 1H), 2.52-2.59 (m, 1H), 3.97 (s, 3H), 4.73-4.93 (m, 2H),7.15 (d, J = 10.4 Hz, 1H), 7.47-7.44 (m, 3H), 7.85 (d, J = 1.2 Hz, 1H),8.02 (d, J = 8.6 Hz, 2H), 9.12 (d, J = 1.2 Hz, 1H). (ESI+) 464.2 (MH+)24B

(CDCl3) δ 1.10-1.17 (m, 2H), 1.41-1.48 (m, 2H), 1.91-2.19 (m, 4H),2.36-2.49 (m, 1H), 2.51-2.65 (m, 4H), 4.71-4.95 (m, 2H), 7.16 (d, J =10.3 Hz, 1H), 7.43-7.49 (m, 3H), 8.01-8.09 (m, 3H), 9.44 (d, J = 1.2 Hz,1H). (ESI+) 480.1 (MH+) 25B

(CDCl3) δ 1.11-1.18 (m, 2H), 1.35 (d, J = 6.1 Hz, 6H), 1.41-1.48 (m,2H), 1.91-2.18 (m, 4H), 2.35-2.48 (m, 1H), 2.51-2.60 (m, 1H), 4.71-4.94(m, 2H), 5.26 (seq, J = 6.1 Hz, 1H), 7.15 (d, J = 10.4 Hz, 1H), 7.40 (s,1H), 7.43 (m, 2H), 7.77 (d, J = 1.2 Hz, 1H), 7.99- (ESI+) 492.2 (MH+)8.04 (m, 2H), 9.09 (d, J = 1.2 Hz, 1H). 26B

(CDCl3) δ 1.14 (ddd, J = 14.1, 6.1, 1.2 Hz, 2H), 1.44 (ddd, J = 9.8,6.7, 1.8 Hz, 2H), 1.94-2.18 (m, 4H), 2.36- 2.47 (m, 1H), 2.52-2.59 (m,1H), 3.43 (s, 3H), 3.73-3.77 (m, 2H), 4.47-4.51 (m, 2H), 4.72-4.91 (m,2H), 7.15 (d, J = 10.4 Hz, 1H), 7.44 (brs, 1H), 7.46 (dt, J = 8.6,(ESI+) 508.2 (MH+) 1.8 Hz, 2H), 7.91 (d, J = 1.2 Hz, 1H), 8.02 (dt, J =8.6 Hz, 1.8 Hz, 2H), 9.09 (d, J = 1.2 Hz, 1H). 27B

(CDCl3) δ 1.08-1.18 (m, 2H), 1.37-1.48 (m, 2H), 1.92-2.18 (m, 6H),2.35-2.48 (m, 1H), 2.50-2.60 (m, 1H), 3.35 (s, 3H), 3.53 (t, J = 6.7 Hz,2H), 4.41 (t, J = 6.7 Hz, 2H), 4.72-4.94 (m, 2H), 7.15 (d, J = 10.4 Hz,1H), 7.43 (brs, 1H), 7.44-7.48 (m, 2H), 7.83 (d, J = 1.8 (ESI+) 522.2(MH+) Hz, 1H), 8.00-8.04 (m, 2H), 9.10 (d, J = 1.2 Hz, 1H).

TABLE 18 28B

(CDCl3) δ 1.11-1.17 (m, 2H), 1.24 (t, J = 7.3 Hz, 3H), 1.41-1.47 (m,2H), 1.91-2.19 (m, 4H), 2.34-2.48 (m, 1H), 2.50-2.60 (m, 1H), 3.58 (q, J= 7.3 Hz, 2H), 3.76-3.81 (m, 2H), 4.44-4.51 (m, 2H), 4.72-4.94 (m, 2H),7.15 (d, J = 10.4 Hz, 1H), 7.41-7.48 (m, 3H), (ESI+) 522.2 (MH+) 7.90(d, J = 1.8 Hz, 1H), 8.00-8.05 (m, 2H), 9.09 (d, J = 1.2 Hz, 1H). 29B

(CDCl3) δ 1.12-1.17 (m, 2H), 1.42-1.46 (m, 2H), 1.94-2.17 (m, 4H), 2.20(s, 3H), 2.37-2.48 (m, 1H), 2.52-2.59 (m, 1H), 2.88 (t, J = 7.0 Hz, 2H),4.51 (t, J = 6.7 Hz, 2H), 4.72-4.93 (m, 2H), 7.15 (d, J = 10.4 Hz, 1H),7.47-7.45 (m, 3H), 7.86 (d, J = 1.2 Hz, 1H), (ESI+) 524.1 (MH+) 8.02 (d,J = 8.6 Hz, 2H), 9.10 (d, J = 1.2 Hz, 1H). 30B

(CDCl3) δ 1.09-1.18 (m, 2H), 1.37-1.48 (m, 2H), 1.48-1.67 (m, 4H),1.68-1.89 (m, 2H), 1.91-2.21 (m, 4H), 2.35-2.48 (m, 1H), 2.51-2.59 (m,1H), 3.46-3.56 (m, 1H), 3.75-3.94 (m, 2H), 4.02-4.10 (m, 1H), 4.45-4.56(m, 2H), 4.68 (t, J = 3.3 Hz, 1H), 4.71-4.95 (m, 2H), 7.15 (d, J = 10.4Hz, 1H), 7.14-7.48 (m, 3H), 7.89 (d, J = 1.2 Hz, 1H), 8.02 (d, J = 8.6Hz, 2H), 9.09 (d, J = 1.2 Hz, 1H). (ESI+) 578.2 (MH+) 31B

(CDCl3) δ 1.09-1.18 (m, 2H), 1.40-1.48 (m, 2H), 1.92-2.19 (m, 4H), 2.32(t, J = 6.1 Hz, 1H), 2.36-2.50 (m, 1H), 2.51-2.60 (m, 1H), 3.94-4.02 (m,2H), 4.44- 4.51 (m, 2H), 4.71-4.95 (m, 2H), 7.15 (d, J = 10.4 Hz, 1H),7.41-7.50 (m, 3H), 7.91 (d, J = 1.2 Hz, 1H), (ESI+) 494.2 (MH+) 8.03 (d,J = 8.8 Hz, 2H), 9.10 (d, J = 1.8 Hz, 1H).

TABLE 19 32B

(DMSO-d6) δ 1.03-1.10 (m, 3H), 1.12-1.16 (m, 2H), 1.40 (s, 3H), 1.44 (s,3H), 1.86-2.01 (m, 2H), 2.10-2.23 (m, 2H), 2.52-2.59 (m, 1H), 2.87-2.93(m, 1H), 3.95 (dd, J = 7.9, 6.7 Hz, 1H), 4.35 (dd, J = 7.9, 6.7 Hz, 1H),4.86-5.05 (m, 2H), 5.18 (t, J = 6.7 Hz, 1H), 6.76 (d, J = 10.4 Hz, 1H),7.49 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 8.49 (d, J = 1.2 Hz,1H), 9.22 (d, J = 1.2 Hz, 1H), 11.0 (s, 1H). (ESI+) 534.2 (MH+) (−) 33B

(DMSO-d6) δ 1.03-1.16 (m, 5H), 1.40 (s, 3H), 1.44 (s, 3H), 1.86-2.01 (m,2H), 2.10-2.22 (m, 2H), 2.53-2.60 (m, 1H), 2.87-2.93 (m, 1H), 3.95 (dd,J = 7.9, 6.7 Hz, 1H), 4.35 (dd, J = 7.9, 6.7 Hz, 1H), 4.85-5.06 (m, 2H),5.18 (t, J = 6.4 Hz, 1H), 6.76 (d, J = 10.4 Hz, 1H), 7.49 (d, J = 8.6Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 8.49 (d, J = 1.8 Hz, 1H), 9.22 (d, J= 1.8 Hz, 1H), 11.0 (s, 1H). (ESI+) 534.2 (MH+) (+) 34B

(DMSO-d6) δ 1.03-1.16 (m, 4H), 1.89-2.01 (m, 2H), 2.09-2.20 (m, 2H),2.52-2.60 (m, 1H), 2.87-2.93 (m, 1H), 3.53-3.59 (m, 1H), 3.65-3.71 (m,1H), 4.63 (q, J = 5.1 Hz, 1H), 4.72 (t, J = 5.8 Hz, 1H), 4.86-5.06 (m,2H), 5.54 (d, J = 4.9 Hz, 1H), 6.75 (d, J = 10.4 Hz, 1H), 7.49 (d, J =8.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 8.46 (d, J = 1.2 Hz, 1H), 9.17(d, J = 1.8 Hz, 1H), 10.9 (s, 1H). (ESI+) 494.2 (MH+) (−) 35B

(DMSO-d6) δ 1.03-1.16 (m, 4H), 1.85-2.01 (m, 2H), 2.10-2.23 (m, 2H),2.53-2.60 (m, 1H), 2.86-2.93 (m, 1H), 3.53-3.59 (m, 1H), 3.65-3.71 (m,1H), 4.63 (q, J = 5.1 Hz, 1H), 4.72 (t, J = 5.8 Hz, 1H), 4.85-5.07 (m,2H), 5.53 (d, J = 4.9 Hz, 1H), 6.75 (d, J = 10.4 Hz, 1H), 7.49 (d, J =8.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 8.46 (d, J = 1.2 Hz, 1H), 9.17(d, J = 1.8 Hz, 1H), 10.9 (s, 1H). (ESI+) 494.2 (MH+) (+)

TABLE 20 36B

(CDCl3) δ 1.11-1.19 (m, 2H), 1.36 (t, J = 7.3 Hz, 6H), 1.42-1.48 (m,2H), 1.90-2.21 (m, 4H), 2.37-2.62 (m, 2H), 4.13-4.34 (m, 4H), 4.73-4.97(m, 2H), 7.21 (d, J = 10.4 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.77 (brs,1H), 8.05 (d, J = 8.6 Hz, 2H), 8.72 (s, 1H), 9.78 (s, 1H). (ESI+) 570.2(MH+) 37B

(CDCl3) δ 1.10-1.18 (m, 2H), 1.29 (t, J = 7.3 Hz, 6H), 1.41-1.48 (m,2H), 1.92-2.20 (m, 4H), 2.37-2.61 (m, 2H), 3.36 (s, 1H), 3.42 (s, 1H),4.04-4.16 (m, 4H), 4.71-4.96 (m, 2H), 7.17 (d, J = 10.4 Hz, 1H), 7.46(d, J = 7.9 Hz, 2H), 7.60 (brs, (ESI+) 584.2 (MH+) 1H), 8.03 (d, J = 8.6Hz, 2H), 8.23 (t, J = 1.8 Hz, 1H), 9.55 (s, 1H). 38B

(CDCl3) δ 1.15 (ddd, J = 13.4, 5.5, 1.2 Hz, 2H), 1.44 (ddd, J = 11.4.5.5, 1.2 Hz, 2H), 1.91-2.14 (m, 4H), 2.31-2.42 (m, 1H), 2.52-2.59 (m,1H), 3.76 (s, 3H), 4.70-4.91 (m, 2H), 6.77 (d, J = 2.5 Hz, 1H), (ESI+)436.2 (MH+) 7.13 (d, J = 10.4 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.43(d, J = 8.6 Hz, 2H), 7.47 (brs, 1H), 7.99 (d, J = 8.0 Hz, 2H). 39B

(CDCl3) δ 1.12-1.18 (m, 2H), 1.39-1.46 (m, 5H), 1.91-2.14 (m, 4H),2.32-2.43 (m, 1H), 2.53-2.59 (m, 1H), 4.01 (q, J = 7.1 Hz, 2H),4.70-4.92 (m, 2H), 6.77 (d, J = 1.8 Hz, 1H), 7.12 (d, J = 10.4 Hz, 1H),(ESI+) 450.2 (MH+) 7.30 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H),7.51 (s, 1H), 7.99 (d, J = 8.6 Hz, 2H). 40B

(CDCl3) δ 1.12-1.17 (m, 2H), 1.42-1.46 (m, 2H), 1.92-2.14 (m, 4H),2.33-2.44 (m, 1H), 2.52-2.59 (m, 1H), 4.25 (dt, J = 26.5, 4.7 Hz, 2H),4.67 (dt, J = 47.1, 4.9 Hz, 2H), 4.71-4.92 (m, 2H), 6.82 (d, J = (ESI+)468.2 (MH+) 2.4 Hz, 1H), 7.12 (d, J = 10.4 Hz, 1H), 7.37 (d, J = 2.4 Hz,1H), 7.44 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 8.00 (d, J = 8.6 Hz, 2H).

TABLE 21 41B

(DMSO-d6) δ 1.01-1.17 (m, 4H), 1.81-1.97 (m, 2H), 2.07-2.21 (m, 2H),2.48-2.57 (m, 1H), 2.85-2.91 (m, 1H), 3.70 (q, J = 5.5 Hz, 2H), 4.03 (t,J = 5.5 Hz, 2H), 4.84-5.05 (m, 3H), 6.44 (d, J = 2.4 Hz, (ESI+) 466.2(MH+) 1H), 6.57 (d, J = 10.4 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.56 (d,J = 2.4 Hz, 1H), 7.89 (d, J = 8.6 Hz, 2H), 10.6 (s, 1H). 42B

(CDCl3) δ 1.09-1.17 (m, 8H), 1.41-1.46 (m, 2H), 1.92-2.15 (m, 4H),2.33-2.44 (m, 1H), 2.53-2.60 (m, 1H), 3.27 (s, 1H), 3.91 (s, 2H),4.72-4.92 (m, 2H), 6.83 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 10.4 Hz, 1H),7.33 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), (ESI+) 494.2 (MH+)7.51 (s, 1H), 8.01 (d, J = 7.9 Hz, 2H). 43B

(CDCl3) δ 1.12-1.17 (m, 2H), 1.32 (s, 3H), 1.37 (s, 3H), 1.42-1.47 (m,2H), 1.91-2.13 (m, 4H), 2.32-2.41 (m, 1H), 2.52-2.59 (m, 1H), 3.68 (dd,J = 8.9, 6.4 Hz 1H), 4.01 (dd, J = 8.6, 6.4 Hz 1H), 4.06-4.08 (m, 2H),4.33-4.39 (m, 1H), 4.72-4.92 (m, 2H), 6.80 (d, J = 2.4 Hz, 1H), 7.11 (d,J = 11.0 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H),7.47 (s, 1H), 8.00 (d, J = 7.9 Hz, 2H). (ESI+) 536.2 (MH+) (+) 44B

(CDCl3) δ 1.12-1.17 (m, 2H), 1.32 (s, 3H), 1.36 (s, 3H), 1.42-1.47 (m,2H), 1.91-2.15 (m, 4H), 2.33-2.43 (m, 1H), 2.52-2.59 (m, 1H), 3.68 (dd,J = 8.6, 6.1 Hz 1H), 4.01 (dd, J = 8.6, 6.1 Hz 1H), 4.06-4.08 (m, 2H),4.33-4.39 (m, 1H), 4.72-4.91 (m, 2H), 6.80 (d, J = 2.4 Hz, 1H), 7.11 (d,J = 10.4 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H),7.47 (s, 1H), 8.00 (d, J = 7.9 Hz, 2H). (ESI+) 536.2 (MH+) (−)

TABLE 22 45B

(DMSO-d6) δ 1.03-1.16 (m, 4H), 1.81-1.98 (m, 2H), 2.06-2.21 (m, 2H),2.51-2.55 (m, 1H), 2.85-2.91 (m, 1H), 3.25-3.35 (m, 2H), 3.73-3.80 (m,1H), 3.87 (dd, J = 13.4, 7.9 Hz 1H), 4.09 (dd, J = 13.8, 4.0 Hz 1H),4.69 (t, J = 5.5 Hz, 1H), 4.85-5.05 (ESI+) 496.2 (MH+) (+) (m, 3H), 6.44(d, J = 1.8 Hz, 1H), 6.58 (d, J = 10.4 Hz, 1H), 7.44 (d, J = 8.6 Hz,2H), 7.53 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 8.6 Hz, 2H), 10.6 (s, 1H).46B

(DMSO-d6) δ 1.03-1.16 (m, 4H), 1.81-1.98 (m, 2H), 2.08-2.23 (m, 2H),2.48-2.56 (m, 1H), 2.85-2.92 (m, 1H), 3.24-3.35 (m, 2H), 3.73-3.81 (m,1H), 3.87 (dd, J = 13.4, 7.9 Hz 1H), 4.09 (dd, J = 13.8, 4.0 Hz 1H),4.69 (t, J = 5.8 Hz, 1H), 4.85-5.05 (ESI+) 496.2 (MH+) (−) (m, 3H), 6.44(d, J = 2.4 Hz, 1H), 6.58 (d, J = 10.4 Hz, 1H), 7.44 (d, J = 8.6 Hz,2H), 7.53 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 8.6 Hz, 2H), 10.6 (s, 1H).47B

(CDCl3) δ 1.13-1.19 (m, 2H), 1.42-1.47 (m, 2H), 1.91-2.15 (m, 4H),2.36-2.47 (m, 1H), 2.53-2.60 (m, 1H), 4.73-4.94 (m, 2H), 7.14 (d, J =1.8 Hz, 1H), 7.18 (d, J = 10.4 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.80(s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 8.31 (d, J = (ESI+) 423.1 (MH+) 1.8Hz, 2H). 48B

(CDCl3) δ 1.17-1.22 (m, 2H), 1.45-1.50 (m, 2H), 1.95-2.17 (m, 4H),2.39-2.50 (m, 1H), 4.74-4.95 (m, 2H), 7.32-7.36 (m, 2H), 7.43 (dd, J =7.9 Hz, 1.2 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 1H),7.85 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 8.6 Hz, 2H), 8.60 (s, 1H). (ESI+)489.1 (MH+) 49B

(CDCl3) δ 1.16-1.22 (m, 2H), 1.45-1.49 (m, 2H), 1.95-2.17 (m, 4H),2.38-2.49 (m, 1H), 2.56-2.62 (m, 1H), 3.87 (s, 3H), 4.74-4.94 (m, 2H),7.03 (dd, J = 9.2, 2.4 Hz, 1H), 7.33-7.30 (m, 2H), 7.46 (d, J = 7.9 Hz,2H), 7.57 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 7.9 Hz, 2H), 8.53 (s, 1H).(ESI+) 519.1 (MH+)

TABLE 23 50B

(CDCl3) δ 1.16-1.22 (m, 2H), 1.45-1.50 (m, 2H), 1.95-2.17 (m, 4H),2.40-2.50 (m, 1H), 2.56-2.63 (m, 1H), 3.87 (s, 3H), 4.74-4.94 (m, 2H),6.54 (t, J = 73.7 Hz, 1H), 7.23 (dd, J = 8.6, 2.4 Hz, 1H), 7.34 (d, J =10.4 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.65(d, J = 9.2 Hz, 1H), 8.06 (d, (ESI+) 555.1 (MH+) J = 8.6 Hz, 2H), 8.56(s, 1H). 51B

(CDCl3) δ 1.16-1.22 (m, 2H), 1.45-1.50 (m, 2H), 1.97-2.13 (m, 4H),2.39-2.50 (m, 1H), 2.56-2.62 (m, 1H), 4.75-4.95 (m, 2H), 7.16 (td, J =9.0, 2.6 Hz, 1H), 7.33 (d, J = 10.4 Hz, 1H), 7.47 (d, J = 7.9 Hz, 2H),7.53 (dd, J = 7.9, 2.4 Hz, 1H), 7.62 (dd, J = 9.2, 4.3 Hz, 1H), 8.06 (d,J = 8.6 Hz, 2H), 8.56 (s, 1H). (ESI+) 507.1 (MH+) 52B

(CDCl3) δ 1.17-1.22 (m, 2H), 1.40 (d, J = 6.1 Hz, 6H), 1.45-1.50 (m,2H), 1.96-2.20 (m, 4H), 2.40-2.51 (m, 1H), 2.56-2.60 (m, 1H), 4.76-4.81(m, 1H), 4.89-4.95 (m, 1H), 5.28 (sep, J = 6.1 Hz, 1H), 7.36 (d, J =11.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.6 Hz, 1H), 8.07(d, J = 8.0 Hz, (ESI+) 575.2 (MH+) 2H), 8.12 (dd, J = 8.3, 1.5 Hz, 1H),8.56 (d, J = 1.5 Hz, 1H), 8.62 (s, 1H). 53B

(CDCl3) δ 1.14-1.22 (m, 2H), 1.44-1.50 (m, 2H), 1.94-2.20 (m, 4H),2.39-2.53 (m, 1H), 2.55-2.63 (m, 1H), 4.73-4.96 (m, 2H), 7.32-7.40 (m,2H), 7.45-7.50 (m, 2H), 7.92 (d, J = 7.9, 1.5 Hz, 1H), 8.04-8.08 (m,2H), 8.46-8.54 (m, 2H). (ESI+) 490.1 (MH+) 54B

(CD3OD) δ 0.99 (t, J = 7.3 Hz, 3H), 1.03-1.17 (m, 2H), 1.20-1.33 (m,2H), 1.42-1.57 (m, 2H), 1.69-1.84 (m, 2H), 1.89-2.07 (m, 2H), 2.12-2.28(m, 2H), 2.61-2.77 (m, 2H), 4.33 (t, J = 6.7 Hz, 2H), 4.77-4.97 (m, 2H),6.82 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 10.4 Hz, 1H), 7.51-7.58 (m, 2H),7.92 (d, J = (ESI+) 562.2 (MH+) 8.6 Hz, 1H), 7.92-8.02 (m, 2H).

TABLE 24 55B

(CDCl3) δ 1.15-1.22 (m, 2H), 1.43-1.50 (m, 2H), 1.92-2.19 (m, 4H),2.37-2.50 (m, 1H), 2.54-2.63 (m, 1H), 3.45 (s, 3H), 3.76-3.80 (m, 2H),4.52- 4.58 (m, 2H), 4.73-4.95 (m, 2H), 6.88 (d, J = 9.2 Hz, 1H), 7.32(d, J = 10.4 Hz, 1H), 7.44-7.49 (m, 2H), 7.79 (d, J = 9.2 Hz, 1H),8.03-8.08 (m, 2H), 8.39 (brs, 1H). (ESI+) 564.2 (MH+) 56B

(CDCl3) δ 1.15-1.22 (m, 2H), 1.30 (t, J = 7.3 Hz, 3H), 1.44-1.50 (m,2H), 1.92-2.19 (m, 4H), 2.36-2.50 (m, 1H), 2.55-2.63 (m, 1H), 4.26 (q, J= 7.3 Hz, 2H), 4.73-4.98 (m, 4H), 6.95 (d, J = 8.6 Hz, 1H), 7.32 (d, J =10.4 Hz, 1H), 7.45-7.49 (m, 2H), 7.84 (d, J = 8.6 Hz, 1H), 8.03-8.08 (m,2H), 8.39 (brs, 1H). (ESI+) 592.1 (MH+)

TABLE 25 Compound Optical No. Structure (A) 1H NMR (400 MHz) MS (m/z)rotation 57B

(DMSO-d6) δ 1.04-1.09 (m, 2H), 1.13-1.18 m, 2H), 1.84-2.00 (m, 2H),2.09-2.24 (m, 2H), 2.50-2.60 (m, 1H), 2.88-2.93 (m, 1H), 3.42-3.51 (m,1H), 3.62-3.71 (m, 1H), 4.54-4.58 (m, 1H), 4.65 (t, J = 5.8 Hz, 1H),4.86-4.94 (m, 1H), 4.98-5.07 (m, 1H), 5.26 (d, J = 4.9 Hz, 1H), 6.81 (d,J = 10.4 Hz, 1H), 6.95 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.90 (d, J =8.6 Hz, 2H). (ESI+) 499.1 (MH+) (+) 58B

(DMSO-d6) δ 1.04-1.09 (m, 2H), 1.13-1.18 (m, 2H), 1.84-2.00 (m, 2H),2.09-2.24 (m, 2H), 2.50-2.60 (m, 1H), 2.88-2.93 (m, 1H), 3.42-3.51 (m,1H), 3.62-3.71 (m, 1H), 4.54-4.58 (m, 1H), 4.65 (t, J = 5.8 Hz, 1H),4.86-4.94 (m, 1H), 4.98-5.07 (m, 1H), 5.26 (d, J = 4.9 Hz, 1H), 6.81 (d,J = 10.4 Hz, 1H), 6.95 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.90 (d, J =8.6 Hz, 2H). (ESI+) 499.1 (MH+) (−) 59B

(CDCl3) δ 1.13-1.19 (m, 2H), 1.45 (s, 3H), 1.45-1.47 (m, 2H), 1.47 (s,3H), 1.93-2.17 (m, 4H), 2.38-2.50 (m, 1H), 2.54-2.61 (m, 1H), 3.04-3.12(m, 1H), 4.02 (dd, J = 22.0, 10.4 Hz, 2H), 4.04 (dd, J = 22.0, 10.4 Hz,2H), 4.73-4.83 (m, 1H), 4.86-4.95 (m, 1H), 6.79 (s, 1H), 7.24 (d, J =10.4 Hz, 1 H), 7.44 (d, J = 7.9 Hz, 2H), 8.05 (d, J = 7.9 Hz, 2H), 8.40(s, 1H). (ESI+) 553.2 (MH+)

TABLE 26 60B

(CDCl3) δ 1.12-1.19 (m, 2H), 1.42-1.48 (m, 2H), 1.94-2.18 (m, 4H),2.39-2.52 (m, 1H), 2.54-2.62 (m, 1H), 3.02-3.10 (m, 1H), 3.94 (s, 2H),3.95 (s, 2H), 4.74-4.82 (m, 1H), 4.87-4.96 (m, 1H), 6.79 (s, 1H), 7.24(d, J = 10.4 Hz, 1 H), 7.45 (d, J = 7.9 Hz, 2H), 8.05 (d, J = 8.6 Hz,2H), 8.52 (s, 1H). (ESI+) 513.1 (MH+) 61B

(CDCl3) δ 1.15-1.20 (m, 2H), 1.44-1.81 (m, 10H), 1.98-2.17 (m, 4H),2.36-2.48 (m, 1H), 2.55-2.61 (m, 1H), 2.91 (t, J = 6.7 Hz, 2H),3.43-3.48 (1H, m), 3.62-3.68 (m, 1H), 3.73-3.79 (m, 1H), 3.94-4.00 (1H,m), 4.57 (t, J = 3.7 Hz, 1H), 4.73-4.94 (m, 2H), 6.71 (s, 1H), 7.25 (d,J = 9.2 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H),8.51 (1H, S). (ESI+) 567.2 (MH+) 62B

(DMSO-d6) δ 1.04-1.10 (m, 2H), 1.12-1.16 (m, 2H), 1.90-1.98 (m, 2H),2.53-2.62 (m, 1H), 2.75 (t, J = 6.7 Hz, 2H), 2.86-2.93 (1H, m), 3.67 (q,J = 6.5 Hz, 2H), 4.62 (t, J = 5.1 Hz, 1H), 4.85-5.08 (m, 2H), 6.83-6.79(m, 2H), 7.46 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 12.4 (s,1H). (ESI+) 483.1 (MH+) 63B

(CDCl3) δ 1.15-1.20 (m, 2H), 1.44-1.48 (m, 2H), 1.94-2.17 (m, 4H),2.41-2.50 (m, 1H), 2.54-2.61 (m, 1H), 2.79 (s, 6H), 4.75-4.96 (m, 2H),7.31 (d, J = 10.4 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.84 (s, 1H), 8.06(d, J = 8.6 Hz, 2H), 8.69 (s, 1H). (ESI+) 546.1 (MH+) 64B

(CDCl3) δ 1.17-1.26 (m, 2H), 1.31 (t, J = 6.7 Hz, 6H), 1.44-1.51 (m,2H), 1.89-2.17 (m, 4H), 2.33-2.48 (m, 1H), 2.57-2.68 (m, 1H), 4.04-4.24(m, 4H), 4.71-4.96 (m, 2H), 7.32 (d, J = 10.4 Hz, 1H), 7.40-7.45 (m,2H), 7.76 (d, J = 4.9 Hz, 1H), 8.03-8.08 (m, 2H), 8.57 (brs, 1H). (ESI+)575.1 (MH+)

TABLE 27 65B

(CDCl3) δ 1.13-1.21 (m, 2H), 1.35 (t, J = 7.3 Hz, 6H), 1.42-1.49 (m,2H), 1.89-2.21 (m, 4H), 2.37-2.52 (m, 1H), 2.52-2.64 (m, 1H), 4.06-4.25(m, 4H), 4.71-4.97 (m, 2H), 7.29 (d, J = 10.4 Hz, 1H), 7.44 (d, J = 7.9Hz, 2H), 7.91 (d, J = 4.9 Hz, 1H), 8.04 (d, J = 7.9 Hz, 2H), 8.79 (brs,1H). (ESI+) 575.1 (MH+) 66B

(DMSO-d6) δ 1.02-1.18 (m, 4H), 1.79-2.01 (m, 2H), 2.06-2.27 (m, 2H),2.38-2.64 (m, 1H), 2.83-2.95 (m, 1H), 4.83-5.09 (m, 2H), 6.88 (d, J =10.4 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 4.9 Hz, 1H), 7.91(d, J = 7.9 Hz, 2H), 12.7 (brs, 1H). (ESI+) 473.1 (MH+) 67B

(CDCl3) δ 1.14-1.19 (m, 2H), 1.42-1.48 (m, 2H), 1.92-2.16 (m, 4H),2.36-2.48 (m, 1H), 2.53-2.61 (m, 1H), 3.02 (t, J = 6.1 Hz, 2H), 3.86 (q,J = 5.5 Hz, 2H), 4.73-4.94 (m, 2H), 7.17 (s, 1H), 7.24 (m, 1H), 7.43 (d,J = 8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 8.42 (s, 1H). (ESI+) 483.1(MH+) 68B

(CDCl3) δ 1.15-1.20 (m, 2H), 1.32 (t, J = 7.0 Hz, 6H), 1.42-1.48 (m,2H), 1.92-2.16 (m, 4H), 2.34-2.48 (m, 1H), 2.52-2.61 (m, 1H), 3.27 (d, J= 20.8 Hz, 2H), 4.10 (dd, J = 7.0 Hz, 2H), 4.13 (dd, J = 7.0 Hz, 2H),4.73-4.82 (m, 1H), 4.85-4.95 (m, 1H), 7.26 (d, J = 10.4 Hz, 1H), 7.43(d, J = 7.9 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 8.43 (s, 1H). (ESI+)589.1 (MH+) 69B

(DMSO-d6) δ 1.15-1.18 (m, 2H), 1.43-1.47 (m, 2H), 1.92-2.17 (m, 4H),2.29 (s, 3H), 2.33-2.70 (m, 6H), 3.67 (s, 2H), 4.73-4.81 (m, 1H),4.85-4.95 (m, 1H), 7.19 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.43 (d, J =8.6 Hz, 2H), 8.02 (d, J = 8.6 Hz, 2H). (ESI+) 551.2 (MH+)

TABLE 28 70B

(CDCl3) δ 1.16-1.19 (m, 2H), 1.44-1.48 (m, 11H), 1.92-2.19 (m, 4H),2.34-2.50 (m, 1H), 2.53-2.62 (m, 1H), 2.84 (t, J = 6.1 Hz, 2H), 3.30 (t,J = 6.1 Hz, 2H), 4.73-4.96 (m, 3H), 7.26-7.28 (m, 1H), 7.41 (s, 1H),7.43 (d, J = 8.6 Hz, 2H), 8.04 (d, J = 8.6 Hz, 2H), 8.43 (s, 1H). (ESI+)558.1 (M+) 71B

(CDCl3) δ 1.17-1.18 (m, 2H), 1.44-1.46 (m, 2H), 1.91-2.18 (m, 4H),2.37-2.49 (m, 1H), 2.52-2.61 (m, 1H), 2.78-2.91 (m, 4H), 4.73-4.96 (m,2H), 7.27 (d, J = 10.4 Hz, 1H), 7.40 (s, 1H), 7.40 (d, J = 8.6 Hz, 2H),8.03 (d, J = 8.6 Hz, 2H). (ESI+) 513.1 (M+) 72B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.44-1.47 (m, 2H), 1.92-2.17 (m, 4H), 2.24(s, 6H), 2.37-2.46 (m, 1H), 2.51-2.60 (m, 2H), 2.85 (t, J = 7.5 Hz, 2H),4.73-4.81 (m, 1H), 4.86-4.94 (m, 1H), 7.27 (d, J = 9.8 Hz, 1H), 7.43 (d,J = 7.9 Hz, 2H), 8.03 (d, J = 7.9 Hz, 2H), 8.45 (s, 1H). (ESI+) 542.1(M+) 73B

(CDCl3) δ 0.95-1.05 (m, 6H), 1.14-1.20 (m, 2H), 1.42-1.48 (m, 2H),1.93-2.18 (m, 4H), 2.36-2.48 (m, 1H), 2.48-2.61 (m, 5H), 2.66-2.76 (m,2H), 2.78-2.89 m, 2H), 4.73-4.94 (m, 2H), 7.26-7.29 (m, 1H), 7.39 (s,1H), 7.43 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 8.40 (s, 1H).(ESI+) 570.2 (M+) 74B

(CDCl3) δ 1.13-1.21 (m, 2H), 1.43-1.49 (m, 2H), 1.79 (brs, 4H),1.92-2.18 (m, 4H), 2.35-2.62 (m, 6H), 2.72 (s, 2H), 2.89 (s, 2H),4.72-4.95 (m, 2H), 7.26-7.29 (m, 1H), 7.39 (s, 1H), 7.43 (d, J = 8.6 Hz,2H), 8.03 (d, J = 8.6 Hz, 2H), 8.38 (s, 1H). (ESI+) 568.2 (M+)

TABLE 29 75B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.42-1.48 (m, 2H), 1.93-2.18 (m, 4H), 2.30(s, 3H), 2.36-2.66 (m, 12H), 2.86 (dd, J = 8.9, 6.4 Hz, 2H), 4.73-4.95(m, 2H) 7.26-7.29 (m, 1H), 7.43 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.6Hz, 2H), 8.39 (s, 1H). (ESI+) 597.2 (MH+) 76B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.43-1.48 (m, 2H), 1.92-2.21 (m, 6H),2.36-2.52 (m, 2H), 2.53-2.61 (m, 1H), 2.71-2.91 (m, 7H), 4.73-4.94 (m,2H), 5.06-5.25 (m, 1H), 7.26-7.29 (m, 1H), 7.40 (s, 1H), 7.43 (d, J =8.6 Hz, 2H), 8.04 (d, J = 8.6 Hz, 2H), 8.38 (s, 1H). (ESI+) 586.1 (MH+)(−) 77B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.43-1.48 (m, 2H), 1.92-2.21 (m, 6H),2.36-2.52 (m, 2H), 2.53-2.61 (m, 1H), 2.71-2.91 (m, 7H), 4.73-4.94 (m,2H), 5.06-5.25 (m, 1H), 7.26-7.29 (m, 1H), 7.40 (s, 1H), 7.43 (d, J =8.6 Hz, 2H), 8.04 (d, J = 8.6 Hz, 2H), 8.38 (s, 1H). (ESI+) 586.1 (MH+)(+) 78B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.42-1.48 (m, 2H), 1.91-2.18 (m, 4H),2.40-2.48 (m, 5H), 2.53-2.63 (m, 3H), 2.87 (dd, J = 8.3, 6.4 Hz, 2H),3.70 (t, J = 4.6 Hz, 4H), 4.73-4.95 (m, 2H), 7.26-7.29 (m, 1H), 7.39 (s,1H), 7.43 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 8.42 (s, 1H).(ESI+) 584.2 (MH+) 79B

(CDCl3) δ 1.13-1.21 (m, 2H), 1.41-1.49 (m, 4H), 1.53-1.57 (m, 4H),1.92-2.22 (m, 4H), 2.37-2.49 (m, 5H), 2.50-2.60 (m, 3H), 2.87 (dd, J =8.9, 6.4 Hz, 2H), 4.72-4.97 (m, 2H), 7.26-7.29 (m, 1H), 7.38 (s, 1H),7.43 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 8.41 (s, 1H). (ESI+)582.2 (MH+)

TABLE 30 80B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.43-1.48 (m, 2H), 1.90-2.18 (m, 8H),2.36-2.49 (m, 1H), 2.50-2.61 (m, 5H), 2.65 (t, J = 7.3 Hz, 2H), 2.86 (t,J = 7.3 Hz, 2H), 4.73-4.95 (m, 2H), 7.26-7.29 (m, 1H), 7.39 (s, 1H),7.43 (d, J = 8.6 Hz, 2H), 8.04 (d, J = 8.6 Hz, 2H), 8.41 (s, 1H). (ESI+)618.2 (MH+) 81B

(CDCl3) δ 1.14-1.21 (m, 2H), 1.42-1.49 (m, 2H), 1.91-2.17 (m, 5H),2.37-2.49 (m, 1H), 2.53-2.61 (m, 1H), 2.92 (t, J = 5.9 Hz, 2H), 3.75 (q,J = 5.9 Hz, 2H), 4.73-4.95 (m, 2H), 7.26-7.29 (m, 1H), 7.42 (s, 1H),7.43 (d, J = 7.9 Hz, 2H), 8.03 (d, J = 7.9 Hz, 2H), 8.45 (s, 1H). (ESI+)515.1 (MH+) 82B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.42-1.48 (m, 2H), 1.70-1.91 (m, 4H),1.91-2.18 (m, 4H), 2.23-2.32 (m, 1H), 2.36-2.49 (m, 1H), 2.53-2.68 (m,3H), 2.84-2.98 (m, 3H), 3.13-3.20 (m, 1H), 3.38 (dd, J = 11.0, 3.1 Hz,1H), 3.60 (dd, J = 11.0, 3.7 Hz, 1H), 4.73-4.95 (m, 2H), 7.26-7.29 (m,1H), 7.41 (s, 1H), 7.43 (d, J = 7.9 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H),8.43 (s, 1H). (ESI+) 598.2 (MH+) 83B

(CDCl3) δ 1.16-1.20 (m, 2H), 1.44-1.48 (m, 2H), 1.91-2.18 (m, 4H),2.37-2.50 (m, 1H), 2.52-2.61 (m, 1H), 3.06 (t, J = 7.0 Hz, 2H), 4.14 (t,J = 7.0 Hz, 2H), 4.77-4.92 (m, 2H), 6.91 (t, J = 1.2 Hz, 1H), 7.06 (s,1H), 7.26-7.30 (m, 1H), 7.39 (s, 1H), 7.44 (d, J = 6.7 Hz, 2H), 8.04 (d,J = 6.7 Hz, 2H), 8.60 (s, 1H). (ESI+) 565.1 (MH+)

TABLE 31 84B

(CDCl3) δ 1.13-1.21 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.42-1.48 (m,2H), 1.67-1.79 (m, 2H), 1.83-1.83 (m, 2H), 1.92-2.18 (m, 6H), 2.20-2.30(m, 1H), 2.35-2.48 (m, 1H), 2.53-2.61 (m, 3H), 2.78-2.89 (m, 4H), 4.12(q, J = 7.1 Hz, 2H), 4.73-4.95 (m, 2H), 7.26-7.30 (m, 1H), 7.38 (s, 1H),7.43 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 8.40 (s, 1H). (ESI+)654.2 (MH+) 85B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.42-1.49 (m, 2H), 1.76-2.19 (m, 8H),2.36-2.48 (m, 1H), 2.57 (tt, J = 7.9, 3.7 Hz, 1H), 2.67-2.73 (m, 1H),2.86 (t, J = 7.0 Hz, 2H), 2.92-2.98 (m, 1H), 3.72 (s, 3H), 4.73-4.95 (m,2H), 7.27 (d, J = 10.4 Hz, 1H), 7.39 (s, 1H), 7.43 (d, J = 8.6 Hz, 2H),8.03 (d, J = 8.6 Hz, 2H), 8.42 (s, 1H). (ESI+) 626.2 (MH+) (−) 86B

(CDCl3) δ 1.14-1.21 (m, 2H), 1.42-1.48 (m, 2H), 1.74 (tt, J = 6.7, 6.7Hz, 2H), 1.92-2.17 (m, 4H), 2.19 (s, 6H), 2.34 (t, J = 7.3 Hz, 2H),2.36-2.47 (m, 1H), 2.57 (tt, J = 7.9, 3.8 Hz, 1H), 2.78 (t, J = 7.3 Hz,2H), 4.73-4.94 (m, 2H), 7.26-7.29 (m, 1H), 7.37 (s, 1H), 7.43 (d, J =8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 8.37 (s, 1H). (ESI+) 556.2 (MH+)87B

(DMSO-d6) δ 1.00-1.18 (m, 4H), 1.62-1.78 (m, 1H), 1.79-2.01 (m, 4H),2.06-2.25 (m, 3H), 2.84-3.04 (m, 4H), 4.82-5.10 (m, 2H), 6.86 (d, J =10.4 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.63 (s, 1H), 7.91 (d, J = 8.6Hz, 2H). (ESI+) 612.1 (MH+) (−)

TABLE 32 88B

(DMSO-d6) δ 1.01-1.20 (m, 4H), 1.42-1.52 (m, 2H), 1.73 (dd, J = 13.1,3.4 Hz, 2H), 1.82-2.01 (m, 4H), 2.08-2.24 (m, 3H), 2.73 (d, J = 11.0 Hz,2H), 2.83 (t, J = 7.3 Hz, 2H), 2.85-2.94 (m, 1H), 4.84-5.08 (m, 2H),6.85 (d, J = 10.4 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.54 (s, 1H), 7.90(d, J = 8.6 Hz, 2H). (ESI+) 648.1 (MH+) 89B

(CDCl3) δ 1.15-1.20 (m, 2H), 1.43-1.48 (m, 2H), 1.91-2.19 (m, 6H),2.35-2.50 (m, 1H), 2.53-2.60 (m, 1H), 2.74-2.92 (m, 6H), 3.04-3.12 (m,2H), 4.71-5.11 (m, 4H), 5.06-5.25 (m, 1H), 7.26-7.29 (m, 1H), 7.39 (s,1H), 7.43 (d, J = 7.9 Hz, 2H), 8.04 (d, J = 8.6 Hz, 2H), 8.42 (s, 1H).(ESI+) 604.1 (MH+) 90B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.31 (s, 3H), 1.42-1.48 (m, 2H), 1.51 (s,3H), 1.92-2.19 (m, 6H), 2.36-2.48 (m, 1H), 2.53-2.61 (m, 1H), 2.66 (dd,J = 8.9, 6.4 Hz, 2H), 2.85 (dd, J = 8.9, 6.4 Hz, 2H), 3.05 (d, J = 11.6Hz, 2H), 4.63 (q, J = 1.4 Hz, 2H), 4.73-4.94 (m, 2H), 7.26-7.29 (m, 1H),7.39 (s, 1H), 7.43 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 8.40(s, 1H). (ESI+) 640.2 (MH+) 91B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.37-1.49 (m, 11H), 1.92-2.17 (m, 4H),2.36-2.49 (m, 1H), 2.54-2.60 (m, 1H), 2.83-2.86 (m, 5H), 3.33-3.46 (m,2H), 4.73-4.95 (m, 2H), 7.26-7.29 (m, 1H), 7.41 (s, 1H), 7.43 (d, J =8.6 Hz, 2H), 8.04 (d, J = 8.6 Hz, 2H), 8.41 (s, 1H). (ESI+) 572.1 (MH+)92B

(CDCl3) δ 1.13-1.20 (m, 2H), 1.42-1.48 (m, 2H), 1.91-2.17 (m, 4H),2.36-2.50 (m, 1H), 2.50-2.62 (m, 3H), 2.63-2.75 (m, 6H), 2.83 (dd, J =7.6, 5.8 Hz, 2H), 4.19 (s, 2H), 4.73-4.95 (m, 2H), 7.26-7.29 (m, 1H),7.39 (s, 1H), 7.43 (d, J = 7.9 Hz, 2H), 8.03 (d, J = 7.9 Hz, 2H), 8.45(s, 1H). (ESI+) 600.1 (MH+)

TABLE 33 93B

(CDCl3) δ 1.13-1.21 (m, 2H), 1.34 (s, 1H), 1.42-1.49 (m, 2H), 1.82-1.89(m, 2H), 1.91-2.18 (m, 4H), 2.34-2.50 (m, 1H), 2.52-2.61 (m, 1H), 2.86(t, J = 7.3 Hz, 2H), 3.76 (q, J = 4.9 Hz, 2H), 4.73-4.95 (m, 2H),7.26-7.29 (m, 1H), 7.42 (s, 1H), 7.43 (d, J = 7.9 Hz, 2H), 8.03 (d, J =7.9 Hz, 2H), 8.43 (s, 1H). (ESI+) 529.1 (MH+) 94B

(CDCl3) δ 1.14-1.21 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.42-1.48 (m,2H), 1.74-2.19 (m, 8H), 2.36-2.49 (m, 2H), 2.52-2.62 (m, 1H), 2.66-2.75(m, 1H), 2.87 (t, J = 7.3 Hz, 2H), 2.92-2.99 (m, 1H), 3.15 (td, J = 8.3,3.6 Hz, 1H), 3.22 (td, J = 9.4, 5.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.8 Hz,1H), 4.73-4.94 (m, 2H), 7.26 (d, J = 11.0 Hz, 1H), 7.39 (s, 1H), 7.43(d, J = 8.5 Hz, 2H), 8.04 (d, J = 8.5 Hz, 2H), 8.39 (s, 1H). (ESI+)534.2 (MH+) (−) 95B

(CDCl3) δ 1.14-1.20 (m, 2H), 1.42-1.49 (m, 2H), 1.92-2.19 (m, 4H),2.38-2.51 (m, 1H), 2.38 (s, 3H), 2.53-2.61 (m, 1H), 2.79 (t, J = 6.1 Hz,2H), 2.89 (t, J = 6.1 Hz, 2H), 4.73-4.95 (m, 2H), 7.26-7.30 (m, 1H),7.39 (s, 1H), 7.43 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H). (ESI+)528.1 (MH+) 96B

(CDCl3) δ 1.14-1.21 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.42-1.48 (m,2H),1.74-2.19 (m, 8H), 2.36-2.49 (m, 2H), 2.52-2.62 (m, 1H), 2.66-2.75(m, 1H), 2.87 (t, J = 7.3 Hz, 2H), 2.92-2.99 (m, 1H), 3.15 (td, J = 8.3,3.6 Hz, 1H), 3.22 (td, J = 9.4, 5.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.8 Hz,1H), 4.73-4.94 (m, 2H), 7.26 (d, J = 11.0 Hz, 1H), 7.39 (s, 1H), 7.43(d, J = 8.5 Hz, 2H), 8.04 (d, J = 8.5 Hz, 2H), 8.39 (s, 1H). (ESI+)640.2 (MH+) (−)

TABLE 34 97B

(CDCl3) δ 1.10-1.18 (m, 2H), 1.41-1.48 (m, 2H), 1.91-2.19 (m, 4H),2.35-2.49 (m, 1H), 2.51-2.61 (m, 1H), 4.70-4.96 (m, 2H), 7.13 (d, J =10.4 Hz, 1H), 7.42-7.48 (m, 2H), 7.67 (brs, 1H), 7.70 (dd, J = 8.6, 2.4Hz, 1H), 8.00-8.05 (m, 2H), 8.16 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 8.6Hz, 1H). (ESI+) 467.1 (MH+) 98B

(CDCl3) δ 1.09-1.19 (m, 2H), 1.40-1.48 (m, 2H), 1.89-2.20 (m, 4H),2.35-2.49 (m, 1H), 2.50-2.61 (m, 1H), 4.71-4.95 (m, 2H), 7.13 (d, J =10.4 Hz, 1H), 7.43-7.51 (m, 3H), 7.67 (brs, 1H), 7.99-8.05 (m, 2H), 8.06(d, J = 3.1 Hz, 1H), 8.33 (dd, J = 9.2, 4.3 Hz, 1H). (ESI+) 451.1 (MH+)99B

(CDCl3) δ 1.41 (t, J = 7.3 Hz, 3H), 1.91-2.19 (m, 4H), 2.33-2.48 (m,1H), 3.15 (s, 3H), 4.04 (q, J = 7.3 Hz, 2H), 4.71-4.94 (m, 2H), 7.11 (d,J = 10.4 Hz, 1H), 7.27 (dd, J = 9.2, 3.1 Hz, 1H), 7.45-7.50 (m, 2H),7.54 (brs, 1H), 7.88 (d, J = 3.1 Hz, 1H), 8.03-8.08 (m, 2H), 8.22 (d, J= 9.2 Hz, 1H). (ESI+) 451.2 (MH+) 100B

(CDCl3) δ 1.09-1.19 (m, 2H), 1.40-1.48 (m, 2H), 1.91-2.19 (m, 4H),2.36-2.50 (m, 1H), 2.50-2.60 (m, 1H), 3.08 (t, J = 6.1 Hz, 1H), 3.36 (t,J = 6.1 Hz, 2H), 3.92 (q, J = 6.1 Hz, 2H), 4.71-4.95 (m, 2H), 7.16 (d, J= 11.0 Hz, 1H), 7.43-7.48 (m, 2H), 7.51 (brs, 1H), 8.01-8.05 (m, 2H),8.15 (d, J = 1.8 Hz, 1H), 9.41 (d, J = 1.8 Hz, 1H). (ESI+) 510.1 (MH+)101B

(CDCl3) δ 1.07-1.17 (m, 2H), 1.41-1.47 (m, 2H), 1.93-2.17 (m, 4H), 2.33(s, 6H), 2.33-2.46 (m, 1H), 2.51-2.59 (m, 1H), 2.71 (t, J = 5.5 Hz, 2H),4.42 (t, J = 5.5 Hz, 2H), 4.72-4.94 (m, 2H), 7.15 (d, J = 10.4 Hz, 1H),7.42 (s, 1H), 7.45 (d; J = 7.9 Hz, 2H), 7.90 (d, J = 1.2 Hz, 1H), 8.02(d. J = 7.9 Hz, 2H), 9.09 (d, J = 1.2 Hz, 1H). (ESI+) 521.2 (MH+)

TABLE 35 102B

(CDCl3) δ 1.11-1.17 (m, 2H), 1.34 (s, 3H), 1.35 (s, 3H), 1.42-1.54 (m,6H), 1.59-1.68 (m, 1H), 1.82-1.93 (m, 1H), 1.93-2.18 (m, 4H), 2.36-2.48(m, 1H), 2.51-2.60 (m, 1H), 3.37-3.95 (m, 1H), 3.88-3.95 (m, 1H), 4.26(dd, J = 15.6, 10.7 Hz, 2H), 4.73-4.94 (m, 3H), 7.15 (d, J = 10.4 Hz,1H), 7.44-7.47 (m, 3H), 7.89 (d, J = 1.2 Hz, 1H), 8.02 (d, J = 7.9 Hz,2H), 9.09 (d, J = 1.2 Hz, 1H). (ESI+) 606.2 (MH+) 103B

(CDCl3) δ 1.11-1.18 (m, 2H), 1.33 (s, 6H), 1.41-1.48 (m, 2H), 1.93-2.18(m, 4H), 2.32 (s, 1H), 2.36-2.49 (m, 1H), 2.52-2.60 (m, 1H), 4.21 (s,2H), 4.73-4.95 (m, 2H), 7.15 (d, J = 11.0 Hz, 1H), 7.49-7.47 (m, 3H),7.92 (d, J = 1.2 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 9.10 (d, J = 1.2 Hz,1H). (ESI+) 521.2 (MH+) 104B

(CDCl3) δ 1.09-1.19 (m, 2H), 1.34-1.49 (m, 2H), 1.42 (s, 9H), 1.89-2.18(m, 4H), 2.31-2.46 (m, 1H), 2.50-2.60 (m, 1H), 3.45 (q, J = 5.5 Hz, 2H),4.07 (t, J = 5.5 Hz, 2H), 4.65 (brs, 1H), 4.71-4.95 (m, 2H), 6.78 (d, J= 2.4 Hz, 1H), 7.11 (d, J = 10.4 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H),7.42-7.46 (m, 2H), 7.50 (brs, 1H), 7.98-8.02 (m, 2H). (ESI+) 565.2 (MH+)105B

(CDCl3) δ 1.09-1.20 (m, 2H), 1.37-1.48 (m, 2H), 1.89-2.18 (m, 4H),2.30-2.46 (m, 1H), 2.50-2.61 (m, 1H), 3.07 (t, J = 5.5 Hz, 2H), 4.02 (t,J = 5.5 Hz, 2H), 4.69-4.94 (m, 2H), 6.79 (d, J = 2.4 Hz, 1H), 7.11 (d, J= 10.4 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.40-7.47 (m, 2H), 7.60 (brs,1H), 7.96-8.03 (m, 2H). (ESI+) 465.2 (MH+)

TABLE 36 106B

(CDCl3) δ 1.12-1.18 (m, 2H), 1.42-1.47 (m, 2H), 1.91-2.15 (m, 4H), 2.23(s, 6H), 2.31-2.43 (m, 1H), 2.52-2.60 (m, 1H), 2.65 (t, J = 6.7 Hz, 2H),4.05 (t, J = 6.7 Hz, 2H), 4.71-4.79 (m, 1H), 4.84-4.92 (m, 1H), 6.77 (d,J = 2.4 Hz, 1H), 7.12 (d, J = 11.0 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H),7.43 (d, J = 8.6 Hz, 2H), 7.51 (s, 1H), 7.99 (d, J = 8.6 Hz, 2H). (ESI+)493.2 (MH+) 107B

(CDCl3) δ 1.12- 1.17 (m, 2H), 1.42-1.46 (m, 2H), 1.49 (s, 6H), 1.91-2.16(m, 4H), 1.97 (s, 6H), 2.34-2.43 (m, 1H), 2.47 (s, 2H), 2.53-2.60 (m,1H), 4.72-4.80 (m, 1H), 4.85-4.93 (m, 1H), 6.75 (d, J = 2.4 Hz, 1H),7.05 (d, J = 10.4 Hz, 1H), 7.05 (d, J = 8.6 Hz, 2H), 7.43 (s, 1H), 7.57(s, 1H), 8.00 (d, J = 8.6 Hz, 2H). (ESI+) 521.2 (MH+) 108B

(CDCl3) δ 1.11-1.23 (m, 2H), 1.40-1.51 (m, 2H), 1.91-2.20 (m, 5H),2.29-2.53 (m, 1H), 2.35 (s, 6H), 2.74 (t, J = 5.5 Hz, 2H), 4.49 (t, J =5.5 Hz, 2H), 4.72-4.96 (m, 2H), 6.87 (d, J = 8.6 Hz, 1H), 7.32 (d, J =10.4 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 8.6 Hz, 1H), 8.05(d, J = 7.9 Hz, 2H). (ESI+) 577.2 (MH+) 109B

(CDCl3) δ 1.15-1.22 (m, 2H), 1.44-1.50 (m, 2H), 1.95-2.20 (m, 4H),2.40-2.52 (m, 1H), 2.55-2.62 (m, 1H), 2.92 (s, 6H), 3.44-3.54 (m, 2H),4.75-4.96 (m, 4H), 6.90 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 10.4 Hz, 1H),7.48 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 8.6 Hz,2H), 8.53 (s, 1H). (ESI+) 577.2 (MH+)

Example 12(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylthio)phenyl]acrylicacid ethyl ester

According to the method described in Example 1,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylthio)phenyl]acrylicacid ethyl ester (773 mg),(Z)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylthio)phenyl]acrylicacid ethyl ester (498 mg), and3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylthio)phenyl]acrylicacid ethyl ester (249 mg) (a mixture of E-form and Z-form) were obtainedfrom (1α,3α,4α)-(3,4-difluorocyclopentyl)methyltriphenylphosphoniumiodide (3.00 g) and 2-[(4-ethylthio)phenyl]oxoacetic acid ethyl ester(1.34 g). Of these compounds, only the title compound was used in thenext step.

¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, J=7.3 Hz, 3H), 1.35 (t, J=7.3 Hz,3H), 1.88-2.18 (m, 4H), 2.55-2.68 (m, 1H), 2.97 (q, J=7.3 Hz, 2H), 4.22(q, J=7.3 Hz, 2H), 4.70-4.96 (m, 2H), 6.97 (d, J=10.4 Hz, 1H), 7.05 (d,J=8.6 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H).

MS (ESI⁺) m/z: 341.1 (MH⁺).

Example 13(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]acrylicacid ethyl ester

According to the method described in Example 2,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]acrylicacid ethyl ester (665 mg) was obtained from(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylthio)phenyl]acrylicacid ethyl ester (730 mg) obtained in Example 12.

¹H NMR (400 MHz, CDCl₃) δ 1.18-1.40 (m, 6H), 1.90-2.20 (m, 4H),2.45-2.58 (m, 1H), 3.16 (q, J=7.3 Hz, 2H), 4.24 (q, J=7.3 Hz, 2H),4.71-4.95 (m, 2H), 7.09 (d, J=10.4 Hz, 1H), 7.35 (d, J=7.9 Hz, 2H), 7.92(d, J=7.9 Hz, 2H).

MS (ESI⁺) m/z: 373.1 (MH⁺).

Example 14(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]acrylicacid

According to the method described in Example 4,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]acrylicacid (420 mg) was obtained from(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]acrylicacid ethyl ester (634 mg) obtained in Example 13.

¹H NMR (400 MHz, CDCl₃) δ 1.33 (t, J=7.3 Hz, 3H), 1.88-2.21 (m, 4H),2.47-2.62 (m, 1H), 3.15 (q, J=7.3 Hz, 2H), 4.71-4.99 (m, 2H), 7.24 (d,J=10.4 Hz, 1H), 7.36 (d, J=7.9 Hz, 2H), 7.93 (d, J=7.9 Hz, 2H).

MS (ESI⁺) m/z: 345.1 (MH⁺).

Example 15 (E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]-N-(thiazol-2-yl)acrylamide(Compound 1C of the Present Invention)

According to the method described in Example 5,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]-N-(thiazol-2-yl)acrylamide(47.4 mg) was obtained from(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(ethylsulfonyl)phenyl]acrylicacid (100 mg) obtained in Example 14 and 2-aminothiazole (29.0 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.42 (t, J=7.3 Hz, 3H), 1.90-2.19 (m, 4H),2.31-2.45 (m, 1H), 3.23 (q, J=7.3 Hz, 2H), 4.69-4.97 (m, 2H), 7.02 (d,J=3.3 Hz, 1H), 7.26 (d, J=10.4 Hz, 1H), 7.42 (d, J=3.3 Hz, 1H), 7.47 (d,J=8.6 Hz, 2H), 8.04 (d, J=8.6 Hz, 2H), 8.54 (brs, 1H).

MS (ESI⁺) m/z: 427.1 (MH⁺).

HRMS (ESI⁺) for C₁₉H₂₁F₂N₂O₃S₂ (MH⁺): calcd., 427.09616; found,427.09624.

Example 16

Compounds 2C and 3C of the present invention were produced according tothe same procedure as in Example 15.

TABLE 37 Compound No. Structure (A) 1H NMR (400 MHz) MS (m/z) 2C

(CDCl3) δ 1.39 (t, J = 7.3 Hz, 3H), 1.91-2.21 (m, 4H), 2.35-2.49 (m,1H), 2.53 (s, 3H), 3.21 (q, J = 7.3 Hz, 2H), 4.71-4.97 (m, 2H), 7.15 (d,J = 10.4 Hz, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.53 (s, 1H), 8.04 (d, J =7.9 Hz, 2H), 8.05 (s, 1H), 9.49 (s, 1H). (ESI+) 436.2 (MH+) 3C

(CDCl3) δ 1.40 (t, J = 7.3 Hz, 3H), 1.85-2.17 (m, 4H), 2.29-2.44 (m,1H), 3.20 (q, J = 7.3 Hz, 2H), 3.75 (s, 3H), 4.66-4.95 (m, 2H), 6.75 (d,J = 2.4 Hz, 1H), 7.11 (d, J = 10.4 Hz, 1H), 7.41-7.50 (m, 3H), 8.00 (d,J = 7.9 Hz, 2H). (ESI+) 424.2 (MH+)

Example 17 2-[4-(2-Methoxyethylthio)phenyl]-2-oxoacetic acid ethyl ester

Ethyl chloroglyoxylate (8.76 mL) was added dropwise to a suspension ofaluminum chloride (13.2 g, crushed) in methylene chloride (127 mL) understirring and cooling with ice, and (2-methoxyethyl)phenylsulfide (12.0g) was added dropwise thereto. The mixture was stirred at roomtemperature for 2 hours. The reaction mixture was poured into ice water(200 mL), and the mixture was stirred for 10 minutes. The organic layerwas separated, washed with a saturated aqueous sodium hydrogen carbonatesolution (40 mL×3), and washed with saturated brine (60 mL). The washedorganic layer was dried over anhydrous sodium sulfate, filtrated, andevaporated under reduced pressure. The obtained residue was purified bycolumn chromatography (silica gel, hexane:ethyl acetate=4:1) to give2-[4-(2-methoxyethylthio)phenyl]-2-oxoacetic acid ethyl ester (1.98 g).

¹H NMR (400 MHz, CDCl₃) δ 1.42 (t, J=7.0 Hz, 3H), 3.23 (t, J=6.7 Hz,2H), 3.39 (s, 3H), 3.65 (t, J=6.7 Hz, 2H), 4.44 (q, J=7.0 Hz, 2H), 7.36(d, J=8.6 Hz, 2H), 7.92 (d, J=8.6 Hz, 2H).

MS (ESI⁺) m/z: 269.1 (MH⁺).

Example 18(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methoxyethylthio)phenyl]acrylicacid ethyl ester

According to the method described in Example 1,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methoxyethylthio)phenyl]acrylicacid ethyl ester (639 mg),(Z)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methoxyethylthio)phenyl]acrylicacid ethyl ester (67 mg), and3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methoxyethylthio)phenyl]acrylicacid ethyl ester (1.01 g) (a mixture of E form and Z form) were obtainedfrom (1α,3α,4α)-(3,4-difluorocyclopentyl)methyl phosphonium iodide (3.00g) and 2-[4-(2-methoxyethylthio)phenyl]-2-oxoacetic acid ethyl ester(1.51 g) obtained in Example 17. Of these compounds, only the titlecompound was used in the next step.

¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, J=7.1 Hz, 3H), 1.86-2.19 (m, 4H),2.54-2.67 (m, 1H), 3.14 (t, J=6.7 Hz, 2H), 3.38 (s, 3H), 3.61 (t, J=6.7Hz, 2H), 4.22 (q, J=7.1 Hz, 2H), 4.71-4.94 (m, 2H), 6.97 (d, J=10.4 Hz,1H), 7.06 (d, J=8.6 Hz, 2H), 7.34 (d, J=8.6 Hz, 2H).

MS (ESI⁺) m/z: 339.1 (MH⁺).

Example 19(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]acrylicacid ethyl ester

According to the method described in Example 2,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]acrylicacid ethyl ester (573 mg) was obtained from(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methoxyethylthio)phenyl]acrylicacid ethyl ester (600 mg) obtained in Example 18.

¹H NMR (400 MHz, CDCl₃) δ 1.29 (t, J=7.1 Hz, 3H), 1.90-2.18 (m, 4H),2.45-2.57 (m, 1H), 3.26 (s, 3H), 3.42 (t, J=6.4 Hz, 2H), 3.79 (t, J=6.4Hz, 2H), 4.23 (q, J=7.1 Hz, 2H), 4.73-4.95 (m, 2H), 7.09 (d, J=10.4 Hz,1H), 7.34 (d, J=8.6 Hz, 2H), 7.92 (d, J=8.6 Hz, 2H).

MS (CI⁺) m/z: 403.1 (MH⁺).

Example 20(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]acrylicacid

According to the method described in Example 4,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]acrylicacid (428 mg) was obtained from(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]acrylicacid ethyl ester (550 mg) obtained in Example 19.

¹H NMR (400 MHz, CDCl₃) δ 1.91-2.19 (m, 4H), 2.49-2.61 (m, 1H), 3.26 (s,3H), 3.42 (t, J=6.1 Hz, 2H), 3.79 (t, J=6.1 Hz, 2H), 4.74-4.96 (m, 2H),7.23 (d, J=10.4 Hz, 1H), 7.35 (d, J=7.9 Hz, 2H), 7.93 (d, J=7.9 Hz, 2H).

MS (CI⁺) m/z: 375.1 (MH⁺).

Example 21(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]-N-(thiazol-2-yl)acrylamide

According to the method described in Example 5,(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]-N-(thiazol-2-yl)acrylamide(44.8 mg) was obtained from(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(2-methoxyethylsulfonyl)phenyl]acrylicacid (100 mg) obtained in Example 20 and 2-aminothiazole (26.7 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.90-2.20 (m, 4H), 2.38-2.52 (m, 1H), 3.31 (s,3H), 3.48 (t, J=5.8 Hz, 2H), 3.87 (t, J=5.8 Hz, 2H), 4.72-4.95 (m, 2H),7.01 (d, J=3.7 Hz, 1H), 7.26 (d, J=10.4 Hz, 1H), 7.40 (d, J=3.7 Hz, 1H),7.45 (d, J=7.9 Hz, 2H), 8.05 (d, J=7.9 Hz, 2H), 8.63 (brs, 1H).

MS (ESI⁺) m/z: 457.1 (MH⁺).

HRMS (ESI⁺) for C₂₀H₂₃F₂N₂O₄S₂ (MH⁺): calcd., 457.10673; found,457.10653.

Example 22

Compounds 2D and 3D of the present invention were produced according tothe same procedure as in Example 21.

TABLE 38 Compound No. Structure (A) 1H NMR (400 MHz) MS (m/z) 2D

(CDCl3) δ 1.90-2.22 (m, 4H), 2.36-2.50 (m, 1H), 2.52 (s, 3H), 3.27 (s,3H), 3.47 (t, J = 5.8 Hz, 2H), 3.84 (t, J = 5.8 Hz, 2H), 4.70-4.95 (m,2H), 7.17 (d, J = 10.4 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.50 (brs,1H), 8.03 (brs, 1H), 8.05 (d, J = 7.9 Hz, 2H), 9.48 (s, 1H). (ESI+)466.2 (MH+) 3D

(CDCl3) δ 1.88-2.16 (m, 4H), 2.30-2.46 (m, 1H), 3.31 (s, 3H), 3.46 (t, J= 5.8 Hz, 2H), 3.75 (s, 3H), 3.85 (t, J = 5.8 Hz, 2H), 4.66-4.96 (m,2H), 6.74 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 11.0 Hz, 1H), 7.25 (d, J =2.4 Hz, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.47 (brs, 1H), 8.02 (d, J = 7.9Hz, 2H). (ESI+) 454.2 (MH+)

Example 23 Ethyl2-(5-{(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide}pyrazin-2-yloxy)acetateFirst Step 5-(4-Methoxybenzyloxy)pyrazin-2-amine

Sodium hydride (60% oily product) (78.8 mg) was added to 4-methoxybenzylalcohol (2.14 mL) at a room temperature in an argon atmosphere, and themixture was stirred for 30 minutes under the same conditions. Next, thereaction mixture was transferred to a metal seal tube. A copper powder(146 mg) and 2-amino-5-bromopyrazine (300 mg) were added, and theresultant mixture was heated and stirred at 160° C. for about 6 hours.After cooling, 25% aqueous ammonia and water were poured into thereaction solution. The reaction mixture was stirred for 1 hour at roomtemperature, and then filtrated through Celite. Water (20 mL) was addedto the filtrate, and the resultant mixture was extracted with ethylacetate (20 mL×3). The organic layer was washed with saturated brine (50mL). The washed organic layer was dried over anhydrous sodium sulfateand filtrated, and then the solvent was removed under reduced pressure.The obtained residue was purified by silica gel column chromatography(elution solvent; hexane:ethyl acetate=3:1) to give5-(4-methoxybenzyloxy)pyrazin-2-amine (104 mg).

¹H NMR (CHCl₃, 400 MHz) •3.81 (s, 3H), 4.12 (brs, 2H), 5.21 (s, 2H),6.90 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 7.56 (d, J=1.2 Hz, 1H),7.79 (d, J=1.2 Hz, 1H).

MS (EI) m/z: 231.1 (M⁺).

HRMS (EI⁺) for C₁₂H₁₃N₃O₂ (M⁺): calcd., 231.1008; found, 231.0988.

Second Step(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(4-methoxybenzyloxy)pyrazin-2-yl]acrylamide

A solution of 5-(4-methoxybenzyloxy)pyrazin-2-amine (90 mg) in anhydrouspyridine (0.49 mL) was added dropwise at a room temperature in an argonatmosphere into a solution of an acid chloride (146 mg) of the(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamideobtained in Example 10 in anhydrous tetrahydrofuran (0.49 mL), and theresultant mixture was stirred for about 2 hours at room temperature.Ethyl acetate was added to the reaction mixture, and the mixture wasthen washed with a 10% citric acid aqueous solution. The organic layerwas washed with a saturated sodium hydrogen carbonate aqueous solution(10 mL×2), and then washed with saturated brine (10 mL). The washedorganic layer was dried over anhydrous sodium sulfate and filtrated, andthen the solvent was removed under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (elutionsolvent; hexane:ethyl acetate=1:1) to give(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(4-methoxybenzyloxy)pyrazin-2-yl]acrylamide(160 mg).

¹H NMR (CHCl₃, 400 MHz) •1.10-1.17 (m, 2H), 1.40-1.48 (m, 2H), 1.94-2.20(m, 4H), 2.36-2.49 (m, 1H), 2.51-2.59 (m, 1H), 3.81 (s, 3H), 4.72-4.94(m, 2H), 5.32 (s, 2H), 6.90 (d, J=8.5 Hz, 2H), 7.15 (d, J=10.3 Hz, 1H),7.38 (d, J=8.5 Hz, 2H), 7.44 (brs, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.86 (d,J=1.2 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 9.13 (d, J=1.2 Hz, 1H).

MS (ESI⁺) m/z: 570.2 (MH⁺).

HRMS (ESI⁺) for C₂₉H₃₀F₂N₃O₅S calcd., 570.18742; found, 570.18681.

Third Step(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-hydroxypyrazin-2-yl)acrylamide

Trifluoroacetic acid (1 mL) was added at a room temperature in an argonatmosphere to a solution of(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-[5-(4-methoxybenzyloxy)pyrazin-2-yl]acrylamide(100 mg) in anhydrous dichloromethane (1 mL), and the resultant mixturewas stirred for 5 minutes. A saturated sodium hydrogen carbonate aqueoussolution was added to the reaction mixture to adjust the pH to 8. Thereaction mixture was then extracted with chloroform (20 mL×2). Theorganic layer was washed with saturated brine (20 mL). The washedorganic layer was then dried over anhydrous sodium sulfate andfiltrated, and then the solvent was removed under reduced pressure. Theobtained residue was purified by silica gel column chromatography(elution solvent; chloroform: acetone=5:1) to give(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-hydroxypyrazin-2-yl)acrylamide(41 mg).

¹H NMR (CHCl₃, 400 MHz) •1.11-1.18 (m, 2H), 1.41-1.48 (m, 2H), 1.92-2.18(m, 4H), 2.36-2.49 (m, 1H), 2.52-2.60 (m, 1H), 4.74-4.95 (m, 2H), 7.11(d, J=10.9 Hz, 1H), 7.28 (brs, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.95 (d,J=1.2 Hz, 1H), 8.03 (d, J=8.5 Hz, 2H), 8.48 (d, J=1.2 Hz, 1H).

MS (ESI³⁰) m/z: 450.1 (MH⁺).

HRMS (ESI⁺) for C₂₁H₂₂F₂N₃O₄S (MH⁺): calcd., 450.12991; found,450.12959.

Fourth Step Ethyl2-(5-{(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide}pyrazin-2-yloxy)acetate

Ethyl bromoacetate (74 μL) and silver oxide (92.9 mg) were added at aroom temperature in an argon atmosphere to a solution of(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-N-(5-hydroxypyrazin-2-yl)acrylamide(150 mg) in anhydrous toluene (5 mL), and the resultant mixture washeated and stirred for about 22 hours at 100° C. in an argon atmosphere.The reaction mixture was cooled, and then filtrated through Celite.After filtration, the solvent was removed under reduced pressure. Theobtained residue was purified by silica gel column chromatography(elution solvent; chloroform: acetone=5:1) to give ethyl2-(5-{(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide}pyrazin-2-yloxy)acetate(35 mg). IR (ATR) 3300, 2983, 1746, 1666, 1603, 1519, 1400, 1375, 1353,1316, 1292, 1208, 1186, 1140, 1087, 1044, 1025, 994, 972 cm⁻¹.

¹H NMR (CHCl₃, 400 MHz) •1.11-1.18 (m, 2H), 1.29 (t, J=7.3 Hz, 3H),1.41-1.48 (m, 2H), 1.92-2.20 (m, 4H), 2.35-2.48 (m, 1H), 2.52-2.60 (m,1H), 4.24 (q, J=7.3 Hz, 2H), 4.73-4.95 (m, 2H), 4.90 (s, 2H), 7.15 (d,J=10.3 Hz, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.47 (brs, 1H), 7.98 (d, J=1.2Hz, 1H), 8.03 (d, J=8.5 Hz, 2H), 9.08 (d, J=1.2 Hz, 1H).

MS (ESI⁺) m/z: 536.2 (MH⁺).

HRMS (ESI⁺) for C₂₅H₂₈F₂N₃O₆S (MH⁺): calcd., 536.16696; found,536.16654.

Example 242-(5-{(E)-2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylamide}pyrazin-2-yloxy)aceticacid

IR (ATR) 3304, 2942, 2535, 1729, 1665, 1609, 1520, 1469, 1437, 1360,1314, 1288, 1239, 1200, 1177, 1141, 1071, 1048, 1028, 994, 973 cm⁻¹.

¹H NMR (DMSO, 400 MHz) •1.00-1.18 (m, 4H), 1.81-2.00 (m, 2H), 2.06-2.25(m, 2H), 2.45-2.60 (m, 1H), 2.85-2.92 (m, 1H), 4.83 (s, 2H), 4.83-5.06(m, 2H), 6.69 (d, J=10.3 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.5Hz, 2H), 8.21 (d, J=1.2 Hz, 1H), 8.72 (d, J=1.2 Hz, 1H), 10.7 (s, 1H),13.0 (brs, 1H).

MS (ESI⁺) m/z: 508.1 (MH⁺).

HRMS (ESI⁺) for C₂₃H₂₄F₂N₃O₆S (MH⁺): calcd., 508.13539; found,508.13523.

Reference Example 1 (1α,3α,4α)-3,4-Difluorocyclopentyl methyl triphenylphosphonium iodide First step[(1α,3β,4β)-3,4-Dihydroxycyclopentyl]methyl benzoate

N-methylmorpholine N-oxide (a 50% aqueous solution, 22.0 mL) and osmiumtetroxide (a 2.5% t-butanol solution, 1.90 mL) were dissolved in acetone(190 mL). A solution of (3-cyclopenten-1-yl)methyl benzoate (WO93/18009,Japanese Translation of PCT International Application No. Hei 7-506816)(20.2 g) in acetone (125 mL) was added dropwise to the prepared solutionover 105 minutes under stirring, and the mixture was stirred at roomtemperature for 15 hours. Chloroform (310 mL) and water (190 mL) wereadded to the reaction mixture, and the organic layer was collected. Thecollected organic layer was washed sequentially with 1 mol/Lhydrochloric acid (2×90 mL), water (90 mL), and a saturated aqueoussodium hydrogen carbonate solution (60 mL), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. Toluene (120 mL) wasadded to the residue, and the precipitated crystals were collected byfiltration to give [(1α,3β,4β)-3,4-dihydroxycyclopentyl]methyl benzoate(16.9 g).

¹H NMR (CDCl₃) δ 1.71-1.78 (m, 2H), 1.95-2.02 (m, 2H), 2.27 (br, 2H),2.75-2.87 (m, 1H), 4.19-4.23 (m, 4H), 7.43-7.47 (m, 2H), 7.55-7.59 (m,1H), 8.01-8.04 (m, 2H).

The filtrate was concentrated under reduced pressure to give a mixtureof [(1α,3β,4β)-3,4-dihydroxycyclopentyl]methyl benzoate and[(1β,3β,4β)-3,4-dihydroxycyclopentyl]methyl benzoate (4.23 g, a ratio ofabout 1:2 determined by the integration ratio of ¹H NMR).

¹H NMR (CDCl₃) δ 1.58-1.65 (m, 1.3H), 1.71-1.78 (m, 0.7H), 1.96-2.17 (m,2H), 2.75-2.85 (m, 1H), 4.09-4.32 (m, 4H), 7.42-7.46 (m, 2H), 7.54-7.59(m, 1H), 8.01-8.06 (m, 2H).

Second Step (3aα,5α,6aα)-(Tetrahydro-4H-cyclopenta-1,3,2-dioxathiol-5-yl)methyl benzoateS,S-dioxide

[(1α,3β,4β)-3,4-Dihydroxycyclopentyl]methylbenzoate (5.00 g) wassuspended in carbon tetrachloride (75 mL). Thionyl chloride (1.90 mL)was added to the suspension, and the mixture was heated for reflux understirring for 1.5 hours. Thionyl chloride (0.50 mL) was further added tothe reaction mixture, and the mixture was heated for reflux understirring for 1 hour. The reaction mixture was concentrated under reducedpressure, and toluene (25 mL) was added to the residue. The mixture wasconcentrated under reduced pressure and dried under reduced pressure togive (3aα,5α,6aα)-(tetrahydro-4H-cyclopenta-1,3,2-dioxathiol-5-yl)methylbenzoate S-oxide (6.09 g). The obtained (3aα,5α,6aα)-(tetrahydro-4H-cyclopenta-1,3,2-dioxathiol-5-yl)methyl benzoateS-oxide (4.27 g) was mixed with acetonitrile (30 mL) and carbontetrachloride (30 mL). Sodium periodate (6.46 g), ruthenium chloridehydrate (31.3 mg), and then water (30 mL) were added to the mixture, andthe resultant mixture was stirred at room temperature for 30 minutes.Dichloromethane (50 mL) was added to the reaction mixture, and insolublematerials were removed by filtration. Then, the organic layer of thefiltrate was separated, and the aqueous layer was extracted withdichloromethane (50 mL). The organic layer and the dichloromethaneextract were combined. The combined solution was washed with a 1 mol/Laqueous sodium thiosulfate solution (2×40 mL) and then with water (2×40mL), dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was dried under reduced pressure to give (3aα,5α,6aα)-(tetrahydro-4H-cyclopenta-1,3,2-dioxathiol-5-yl)methyl benzoateS,S-dioxide (4.35 g).

MS (CI⁺) m/z: 299 (MH⁺).

HRMS (CI⁺) for C₁₃H₁₅O₆S (MH⁺): calcd., 299.0589; found, 299.0593.

Third Step [(1α,3α,4β)-3-Fluoro-4-hydroxycyclopentyl]methyl benzoate

Tetrabutylammonium fluoride hydrate (571 mg) was dissolved in anhydrousacetonitrile (5 mL), and the prepared solution was concentrated underreduced pressure. The same procedure was repeated additional two times,and the residue was dried under reduced pressure at 40° C. for 45minutes. The resultant residue was dissolved in dehydrated acetonitrile(5 mL). (3aα, 5α,6aα)-(Tetrahydro-4H-cyclopenta-1,3,2-dioxathiol-5-yl)methyl benzoate S,S-dioxide (500 mg) was added to the prepared solution,and the mixture was heated to reflux under stirring for 45 minutes.Then, the reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in ethanol (5 mL), and sulfuric acid (0.15 mL) wasadded thereto. The mixture was heated to reflux under stirring for 10minutes, and the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate (40 mL). Theresultant solution was washed with a saturated aqueous sodium hydrogencarbonate solution (5 mL) and then with saturated brine (5 mL), driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(eluent:hexane/ethyl acetate=1:1) to give[(1α,3α,4β)-3-fluoro-4-hydroxycyclopentyl]methyl benzoate (342 mg).

MS (EI) m/z: 238 (M⁺).

HRMS (EI) for C₁₃H₁₅FO₃(M⁺): calcd., 238.1005; found, 238.1046.

Fourth Step [(1α,3α,4α)-3,4-Difluorocyclopentyl]methyl benzoate

[(1α,3α, 4β)-3-Fluoro-4-hydroxycyclopentyl]methyl benzoate (326 mg) wasdissolved in anhydrous tetrahydrofuran (5 mL). A solution ofbis(2-methoxyethyl)amino sulfur trifluoride (455 mg) in anhydroustetrahydrofuran (2 mL) was added to the prepared mixture, and themixture was heated to reflux under stirring for 1.5 hours. The reactionmixture was added to a saturated aqueous sodium hydrogen carbonatesolution (10 mL), and the resultant solution was extracted with ethylacetate (2×30 mL). The ethyl acetate extracts were combined, washed withsaturated brine (2×10 mL), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane/ethyl acetate=4:1) to give[(1α,3α,4α)-3,4-difluorocyclopentyl]methyl benzoate (233 mg).

MS (CI⁺) m/z: 241 (MH⁺).

HRMS (CI⁺) for C₁₃H₁₅F₂O₂(MH⁺): calcd., 241.1040; found, 241.1043.

Fifth Step [(1α,3α,4α)-3,4-difluorocyclopentyl]methanol

[(1α,3α,4α)-3,4-Difluorocyclopentyl]methyl benzoate (221 mg) wasdissolved in ethanol (3 mL). A solution of potassium carbonate (191 mg)in water (1 mL) was added to the prepared solution, and the mixture washeated to reflux under stirring for 4 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane/ethyl acetate=1:2) togive [(1α,3α,4α)-3,4-difluorocyclopentyl]methanol (123 mg).

MS (CI⁺) m/z: 137 (MH⁺).

HRMS (CI⁺) for C₆H₁₁F₂O (MH⁺): calcd., 137.0778; found, 137.0801.

Sixth Step (1α,3α,4α)-3,4-Difluorocyclopentylmethyl iodide

Iodine (120 mg) was added to a solution of imidazole (64.5 mg) andtriphenylphosphine (124 mg) in dichloromethane (2.0 mL) under coolingwith ice, and the mixture was stirred at room temperature for 30minutes. Then, a solution of[(1α,3α,4α)-3,4-difluorocyclopentyl]methanol (43.0 mg) indichloromethane (0.5 mL) was added to the resultant mixture, and themixture was stirred at room temperature for 4 hours, and insolublematerials were removed by filtration. The residue obtained byconcentrating the filtrate was purified by silica gel columnchromatography to give (1α,3α,4α)-3,4-difluorocyclopentylmethyl iodide(28.0 mg).

MS⁻ (EI) m/z: 246 (M⁺).

HRMS (EI) for C₆H₉F₂I (M⁺): calcd., 245.9717; found, 245.9741.

Seventh Step(1α,3α,4α)-(3,4-Difluorocyclopentyl)methyltriphenylphosphonium iodide

(1α,3α,4α)-(3,4-difluorocyclopentyl)methyl iodide (9.84 g),triphenylphosphine (12.6 g), and acetonitrile (3 mL) were mixed andstirred at 90 to 95° C. for 4 hours. Acetonitrile (2 mL) was furtheradded to the reaction mixture, and the mixture was further stirred at 90to 95° C. for 20 hours. After cooling, diethyl ether (50 mL) was addedto the reaction mixture, and the precipitated crystals were collected byfiltration. The collected crystals were suspended in diethyl ether (50mL), and the suspension was filtrated to collect the crystals. Thecollected crystals were washed with an appropriate amount of diethylether and dried under reduced pressure to give the title compound (20g).

¹H NMR (400 MHz, CDCl₃) δ 1.72-1.85 (m, 2H), 2.17-2.29 (m, 2H),2.69-2.82 (m, 1H), 3.86 (dd, J=7.3, 2.4 Hz, 1H), 3.89 (dd, J=7.3, 2.4Hz, 1H), 4.74-4.92 (m, 2H), 7.31-7.90 (m, 15H).

Reference Example 2 2-(5-Aminopyrazin-2-ylthio)ethanol

According to the method described in WO2004/052869,2-hydroxy-1-ethanethiol (0.93 mL) andtetrakis(triphenylphosphine)palladium (3.39 g) were added to a solutionof 2-amino-5-bromopyrazine (1.00 g, 5.75 mmol) in N,N-dimethylformamide(15.1 mL), and the mixture was heated and stirred at 120° C. in a sealedtube for about 3 hours. After cooling, the reaction mixture was dilutedwith water and extracted with a mixed solution(dichloromethane:ethanol=5:1) (100 mL×6). The organic layer was driedover anhydrous sodium sulfate and then filtrated, and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography (hexane:ethyl acetate=1:1, then ethyl acetate, and thenethyl acetate:methanol=10:1) and was recrystallized (using chloroform)to give the title compound as yellow needle crystals (470 mg, yield:44%).

MS (EI⁺) m/z: 171 (M⁺).

HRMS (EI⁺) for C₆H₉N₃OS (M⁺): calcd., 171.0466; found, 171.0451.

Reference Example 3 5-[2-(Methylthio)ethoxy]pyrazin-2-amine

According to the method described in WO2007007886, sodium hydride (50%oily product) (314 mg) was added to methylthioethanol (7.88 mL) undercooling with ice and stirring, and then copper (490 mg) and2-amino-5-bromopyrazine (1.00 g) were added thereto. The reactionmixture was placed in an autoclave and heated and stirred at 160° C. forabout 5 hours. After cooling, the reaction mixture was diluted withwater (50 mL) and ethyl acetate (50 mL), and 25% aqueous ammonia (2 mL)was added to the mixture to make it basic. The reaction mixture wasfiltrated through Celite, and the organic layer and the aqueous layerwere separated. The aqueous layer was extracted with ethyl acetate (50mL×2), and the extracts and the organic layer were combined, dried overanhydrous sodium sulfate, and filtrated. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography (hexane:ethyl acetate=1:1) and then by preparative TLC(chloroform:methanol=10:1, then NH silica gel, hexane:acetone=3:1) togive the title compound as white powder crystals (59.2 mg, yield: 6%).

MS (EI⁺) m/z: 185 (M⁺).

HRMS (EI⁺) for C₇H₁₁N₃OS (M⁺): calcd., 185.0623; found, 185.0613.

Reference Example 4 5-(2-Ethoxyethoxyl)pyrazin-2-amine

According to the method described in Reference Example 3, the titlecompound was obtained as yellow crystals (1.50 g, yield: 41%) from2-amino-5-bromopyrazine (3.48 g) and ethoxyethanol (36.0 g).

MS (EI⁺) m/z: 183 (M⁺).

HRMS (EI⁺) for C₈H₁₃N₃O₂(M⁺): calcd., 183.1008; found, 183.0996

Reference Example 5 5-(3-Methoxypropoxy)pyrazin-2-amine

According to the method described in Reference Example 3, the titlecompound was obtained as yellow crystals (644 mg, yield: 18%) from2-amino-5-bromopyrazine (3.48 g) and methoxypropanol (18.0 g).

MS (EI⁺) m/z: 183 (M⁺).

HRMS (EI⁺) for C₈H₁₃N₃O₂(M⁺): calcd., 183.1008; found, 183.1011.

Reference Example 6 5-[2-(Dimethylamino)ethoxy]pyrazin-2-amine

According to the method described in Reference Example 3, the titlecompound was obtained as a yellow oil (121 mg, yield: 23%) from2-amino-5-bromopyrazine (500 mg) and 2-(dimethylamino) ethanol (2.56 g).

MS (CI) m/z: 183 (MH⁺).

HRMS (CI) for C₈H₁₅N₄O (MH⁺): calcd., 183.1246; found, 183.1242.

¹H NMR (400 MHz, CDCl₃) δ 2.33 (s, 6H), 2.70 (t, J=5.8 Hz, 2H), 4.12(brs, 2H), 4.31 (t, J=5.8 Hz, 2H), 7.53 (d, J=1.2 Hz, 1H), 7.80 (d,J=1.2 Hz, 1H).

IR (ATR): 1280, 1630, 3330 cm⁻¹.

Reference Example 75-[2-Methyl-2-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyrazin-2-amine

According to the method described in Reference Example 3, the titlecompound was obtained as brown powder crystals (60 mg, yield: 13%) from2-amino-5-bromopyrazine (299 mg) and2-methyl-2-[(tetrahydro-2H-pyran-2-yl)oxy]-1-propanol (1.50 g).

MS (CI) m/z: 268 (MH⁺).

HRMS (CI) for C₁₃H₂₂N₃O₃ (MH⁺): calcd., 268.1661; found, 268.1645.

¹H NMR (400 MHz, CDCl₃) δ 1.35 (s, 6H), 1.46-1.52 (m, 4H), 1.59-1.72 (m,1H), 1.76-1.88 (m, 1H), 3.43 (td, J=8.3, 4.3 Hz, 1H), 3.94 (ddd, J=11.6,5.2, 3.7 Hz, 1H), 4.11 (d, J=10.4 Hz, 1H), 4.16 (d, J=10.4 Hz, 1H), 4.21(s, 2H), 4.88 (q, J=2.9 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.79 (d, J=1.8Hz, 1H).

IR (ATR): 1620, 1487, 1379 cm⁻¹.

Reference Example 81-[2-(Dimethylamino)-2-methylpropyl]-1H-pyrazol-3-amine

Sodium hydride (156 mg) was added to a solution of 3-nitro-1H-pyrazole(196 mg) in anhydrous DMF (2 mL) under cooling with ice, and the mixturewas stirred at room temperature for 15 minutes. A solution of1-chloro-N,N,2-trimethylpropan-2-amine in DMF (0.52 mL) was added to theresultant mixture, and the mixture was stirred at room temperature forabout 24 hours. A saturated aqueous ammonium chloride solution (25 mL)and ethyl acetate (25 mL) were added to the reaction mixture and stirredunder cooling with ice. The organic layer was separated, washed withsaturated brine (100 mL), dried over anhydrous sodium sulfate, andfiltrated, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(neutral spherical silica gel, ethyl acetate:hexane=1:1) to giveN,N,2-trimethyl-1-(3-nitro-1H-pyrazol-1-yl)propan-2-amine as yellowpowder crystals (90.9 mg, yield: 25%).

MS (CI) m/z: 213 (MH⁺).

HRMS (CI) for C₉H₁₇N₄O₂ (MH⁺): calcd, 213.1352; found, 213.1314.

N,N,2-trimethyl-1-(3-nitro-1H-pyrazol-1-yl)propan-2-amine (70.6 mg) wasdissolved in a mixed solution (ethanol-ethyl acetate, 4:1, 5 mL). Then,10% palladium-carbon (7 mg) was added to the prepared solution, and thesolution was subjected to catalytic reduction at 101 kPa for about 2hours. The reaction mixture was filtrated through Celite, and thefiltrate was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (silica gel NH, ethylacetate:hexane=1:1) to give the title compound as a yellow oil (56.8 mg,yield: 94%).

MS (CI) m/z: 183 (MH⁺).

HRMS (CI) for C₉H₁₄N₄ (MH⁺): calcd., 183.1610; found, 183.1615.

¹H NMR (400 MHz, CDCl₃) δ 1.50 (s, 6H), 2.03 (s, 6H), 2.53 (s, 2H), 3.59(s, 2H), 5.56 (d, J=2.4 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H).

IR (ATR): 1617, 1541, 1492 cm⁻¹.

Reference Example 9 5-(2-Bromoethylthio)thiazol-2-amine

Triphenylphosphine (12.1 g), imidazole (3.86 g), and carbon tetrabromide(4.44 g) were added to a suspension of5-(2-hydroxyethylthio)thiazol-2-amine (2.00 g) in methylene chloride(74.6 mL) under cooling with ice, and the mixture was stirred undercooling with ice for 4 hours. Methylene chloride (200 mL) and water (100mL) were added to the reaction mixture, and the mixture was extracted.The organic layer was washed with saturated brine (100 mL), dried overanhydrous sodium sulfate, and filtrated, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (neutral spherical silica gel, ethylacetate:hexane=1:10 and then 1:2) and washed with hexane to give thetitle compound as white powder crystals (1.06 g, yield: 39%).

MS (EI) m/z: 238 (M⁺).

HRMS (EI) for C₅H₇BrN₂S₂ (M⁺): calcd, 237.9234; found, 237.9212.

Reference Example 10 5-(3-Bromopropylthio)thiazol-2-amine

According to the method described in Reference Example 9, the titlecompound was obtained as a yellow oil (450 mg, yield: 7%) from5-(3-hydroxypropylthio)thiazol-2-amine (5.00 g).

MS (ESI) m/z: 253 (MH⁺).

HRMS (ESI) for C₆H₁₀BrN₂S₂ (M⁺): calcd, 252.94688; found, 252.94629.

Reference Example 115-[2-(4-Methylpiperazin-1-yl)ethylthio]thiazol-2-amine

1-Methylpiperazine (3.47 mL) was added to the compound obtained inReference Example 9 (150 mg), and the mixture was heated and stirred at60° C. for 2 hours. After cooling, the reaction mixture was concentratedunder reduced pressure. Methylene chloride (10 mL) and a saturatedaqueous sodium hydrogen carbonate solution (10 mL) were added to theresidue, and the mixture was extracted. The extraction was repeatedtwice, and the combined organic layers were washed with saturated brine(7 mL), dried over anhydrous sodium sulfate, filtrated, and evaporatedunder reduced pressure. The obtained amorphous was washed withdiisopropyl ether to give the title compound as white powder crystals(137 mg, yield: 84%).

Melting point 106-108° C.

EIMS m/z: 258 (M⁺).

HRMS (EI) for C₁₀H₁₈N₄S₂ (M⁺): calcd., 258.0973; found, 258.0978.

¹H NMR (400 MHz, CDCl₃) δ 2.28 (s, 3H), 2.35-2.57 (m, 8H), 2.61 (dd,J=8.0, 4.3 Hz, 2H), 2.77 (dd, J=8.0, 4.3 Hz, 2H), 4.95 (s, 2H), 7.09 (s,1H).

IR (ATR): 1653, 1527, 1485 cm⁻¹.

Reference Example 12(S)-5-[2-(3-Fluoropyrrolidin-1-yl)ethylthio]thiazol-2-amine

According to the method described in Reference Example 11, the titlecompound was obtained as white powder crystals (82.3 mg, yield: 40%)from the compound obtained in Reference Example 9 (200 mg), (S)-3-fluoropyrrolidine hydrochloride (210 mg), and triethylamine (0.50 mL).

Melting point 144-145° C.

[α]_(D) ²⁴−4° (c0.41, DMSO)

EIMS m/z: 247 (M⁺).

HRMS (EI) for C₉H₁₄FN₃S₂ (M⁺): calcd, 247.0613; found, 247.0646.

¹H NMR (400 MHz, CDCl₃) δ 1.94-2.22 (m, 2H), 2.42-2.51 (m, 1H),2.70-2.91 (m, 7H), 4.99 (s, 2H), 5.06-5.25 (m, 1H), 7.10 (s, 1H).

IR (ATR): 1649, 1533, 1491 cm⁻¹.

Reference Example 13(R)-5-[2-(3-Fluoropyrrolidin-1-yl)ethylthio]thiazol-2-amine

According to the method described in Reference Example 11, the titlecompound was obtained as white powder crystals (98.8 mg, yield: 48%)from the compound obtained in Reference Example 9 (200 mg), (R)-3-fluoropyrrolidine hydrochloride (210 mg), and triethylamine (0.50 mL).

Melting point 147° C.

[α]_(D) ²³+3° (c0.43, DMSO)

EIMS m/z: 247 (M⁺).

HRMS (EI) for C₉H₁₄FN₃S₂ (M⁺): calcd., 247.0613; found, 247.0622.

¹H NMR (400 MHz, CDCl₃) δ 1.94-2.22 (m, 2H), 2.42-2.51 (m, 1H),2.70-2.91 (m, 7H), 4.99 (s, 2H), 5.06-5.25 (m, 1H), 7.10 (s, 1H).

IR (ATR): 1649, 1533, 1491 cm⁻¹.

Reference Example 145-[2-(4,4-Difluoropiperidin-1-yl)ethylthio]thiazol-2-amine

According to the method described in Reference Example 11, the titlecompound was obtained as white powder crystals (68.9 mg, yield: 30%)from the compound obtained in Reference Example 9 (200 mg),4,4-difluoropiperidine hydrochloride (263 mg), and triethylamine (0.50mL).

Melting point 127° C. (diisopropyl ether)

EIMS m/z: 279 (M⁺).

HRMS (EI) for C₁₀H₁₅F₂N₃S₂ (M⁺): calcd., 279.0675; found, 279.0679.

¹H NMR (400 MHz, CDCl₃) δ 1.93-2.06 (m, 4H), 2.56 (t, J=5.5 Hz, 4H),2.64 (dd, J=8.9, 5.8 Hz, 2H), 2.76 (dd, J=8.9, 5.8 Hz, 2H), 5.21 (s,2H), 7.08 (s, 1H).

IR (ATR): 1609, 1519, 1478 cm⁻¹.

Reference Example 151-[2-(2-Aminothiazol-5-ylthio)ethyl]piperidine-4-carboxylic acid ethylester

According to the method described in Reference Example 11, the titlecompound was obtained as white powder crystals (150 mg, yield: 76%) fromthe compound obtained in Reference Example 9 (150 mg) andpiperidine-4-carboxylic acid ethyl ester (4.83 mL).

Melting point 80-81° C.

MS (CI) m/z: 316 (MH⁺).

HRMS (CI) for C₁₃H₂₂N₃O₂S₂ (MH⁺): calcd., 316.1153; found, 316.1141.

¹H NMR (400 MHz, CDCl₃) δ 1.25 (t, J=7.1 Hz, 3H), 1.68-1.80 (m, 2H),1.82-1.92 (m, 2H), 2.04-2.10 (m, 2H), 2.21-2.31 (m, 1H), 2.55-2.59 (m,2H), 2.75-2.80 (m, 2H), 2.80-2.88 (m, 2H), 4.13 (q, J=7.1 Hz, 2H), 5.00(s, 2H), 7.08 (s, 1H).

IR (ATR): 1707, 1524, 1448 cm⁻¹.

Reference Example 16(S)-[1-[2-(2-Aminothiazol-5-ylthio)ethyl]pyrrolidin-2-yl]methanol

According to the method described in Reference Example 11, the titlecompound was obtained as white powder crystals (130 mg, yield: 80%) fromthe compound obtained in Reference Example 9 (150 mg) and(S)-pyrrolidin-2-ylmethanol (3.10 mL).

Melting point 98-99° C.

[α]_(D) ²⁴−90° (c0.54, CHCl₃).

MS (CI) m/z: 260 (MH⁺).

HRMS (CI) for C₁₀H₁₈N₃OS₂ (MH⁺): calcd., 260.0891; found, 260.0892.

¹H NMR (400 MHz, CDCl₃) δ 1.70-1.95 (m, 4H), 2.27 (q, J=8.6 Hz, 1H),2.53-2.60 (m, 1H), 2.60-2.68 (m, 1H), 2.75-2.83 (m, 2H), 2.90-2.97 (m,1H), 3.14-3.20 (m, 1H), 3.38 (dd, J=11.0, 2.4 Hz, 1H), 3.62 (dd, J=11.0,3.7 Hz, 1H), 4.96 (s, 2H), 7.12 (s, 1H).

IR (ATR): 3161, 1516, 1498 cm⁻¹.

Reference Example 175-[2-[cis-3,4-Difluoropyrrolidin-1-yl]ethylthio]thiazol-2-amine

According to the method described in Reference Example 11, the titlecompound was obtained as white powder crystals (35.0 mg, yield: 19%).More specifically, the compound obtained in Reference Example 9 (200mg), cis-3,4-difluoro pyrrolidine hydrochloride (100 mg), anddiisopropylamine (141 mg) were used for the reaction, and potassiumiodide (12 mg) was added during the reaction.

MS (CI) m/z: 266 (MH⁺).

HRMS (CI) for C₉H₁₄F₂N₃S₂ (MH⁺): calcd., 266.0597; found, 266.0577.

¹H NMR (400 MHz, CDCl₃) δ 2.71-2.80 (m, 4H), 2.81-2.94 (m, 2H),3.04-3.14 (m, 2H), 4.89-5.12 (m, 2H), 5.00 (s, 2H), 7.09 (s, 1H).

IR (ATR): 1645, 1530, 1490 cm⁻¹.

Reference Example 185-[2-(cis-2,2-Dimethyltetrahydro-5H-1,3-dioxolo[4,5-C]pyrrol-5-yl)ethylthio]thiazol-2-amine

According to the method described in Reference Example 11, the titlecompound was obtained as white powder crystals (127 mg, yield: 30%) fromthe compound obtained in Reference Example 9 (330 mg) andcis-2,2-dimethyltetrahydro-5H-1,3-dioxolo[4,5-c]pyrrole (280 mg).

MS (ESI) m/z: 302 (MH⁺).

HRMS (ESI) for C₁₂H₂₀N₃O₂S₂ (MH⁺): calcd., 302.09969; found, 302.09926.

¹H NMR (400 MHz, CDCl₃) δ 1.31 (s, 3H), 1.52 (s, 3H), 2.10-2.17 (m, 2H),2.62-2.66 (m, 2H), 2.74-2.78 (m, 2H) 3.06 (d, J=11.6 Hz, 2H), 4.62-4.65(m, 2H), 4.96 (s, 2H), 7.08 (s, 1H).

IR (ATR): 1644, 1513, 1483 cm⁻¹.

Reference Example 19(S)-1-[2-(2-Aminothiazol-5-ylthio)ethyl]pyrrolidine-2-carboxylic acidmethyl ester

According to the method described in Reference Example 11, the titlecompound was obtained as a yellow oil (85.7 mg, yield: 36%) from thecompound obtained in Reference Example 9 (200 mg),(S)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (277 mg),and triethylamine (0.50 mL).

[α]_(D) ²⁵ −85° (c0.25, CHCl₃).

MS (CI) m/z: 288 (MH⁺).

HRMS (CI) for C₁₁H₁₈N₃O₂S₂ (MH⁺): calcd., 288.0840; found, 288.0837.

¹H NMR (400 MHz, DMSO-d₆) δ 1.74-1.87 (m, 1H), 1.87-2.00 (m, 2H),2.04-2.18 (m, 1H), 2.41 (q, J=8.2 Hz, 1H), 2.66-2.72 (m, 1H), 2.77 (dd,J=7.9, 6.7 Hz, 2H), 2.90-2.96 (m, 1H), 3.15 (td, J=8.3, 3.1 Hz, 1H),3.23 (dd, J=8.6, 5.5 Hz, 1H), 3.71 (s, 3H), 5.00 (s, 2H), 7.10 (s, 1H).

IR (ATR): 3293, 3124, 2949, 2815, 1732, 1517, 1484 cm⁻¹.

Reference Example 20(S)-1-[2-(2-Aminothiazol-5-ylthio)ethyl]pyrrolidine-2-carboxylic acidethyl ester

According to the method described in Reference Example 11, the titlecompound was obtained as a yellow oil (580 mg, yield: 58%) from thecompound obtained in Reference Example 9 (800 mg),(S)-pyrrolidine-2-carboxylic acid ethyl ester hydrochloride (15 g), andisopropylamine (9.00 g).

[α]_(D) ²⁵ −61° (c0.28, CHCl₃).

MS (CI) m/z: 302 (MH⁺).

HRMS (CI) for C₁₂H₂₀N₃O₂S₂ (MH⁺): calcd., 302.0997; found, 302.1012.

¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (t, J=6.7 Hz, 3H), 1.74-1.85 (m, 1H),1.85-2.00 (m, 2H), 2.05-2.18 (m, 1H), 2.38-2.48 (m, 1H), 2.66-2.72 (m,1H), 2.77 (t, J=7.3 Hz, 2H), 2.90-2.97 (m, 1H), 3.13-3.22 (m, 2H), 4.17(qd, J=7.3, 1.2 Hz, 2H), 5.35 (s, 2H), 7.07 (s, 1H).

IR (ATR): 1728, 1619, 1517 cm⁻¹.

Reference Example 21 5-[3-(Dimethylamino)propylthio]thiazol-2-amine

According to the method described in Reference Example 11, the titlecompound was obtained as colorless powder crystals (53.5 mg, yield: 62%)from the compound obtained in Reference Example 10 (100 mg) anddimethylamine (a 2M methanol solution, 9.90 mL).

MS (APCI) m/z: 216 (MH⁺).

HRMS (APCI) for C₈H₁₄N₃S₂ (MH⁺): calcd., 216.06291; found, 216.06354.

¹H NMR (400 MHz, CDCl₃) δ1.72-1.79 (m, 2H), 2.20 (s, 6H), 2.35 (t, J=7.3Hz, 2H), 2.68 (t, J=7.3 Hz, 2H), 5.26 (s, 2H), 7.07 (s, 1H).

IR (ATR): 1647, 1514, 1493 cm⁻¹.

Reference Example 22 Ethyl(Z)-3-(1α,3α,4α)-3,4-(difluorocyclopentyl)acrylate

Lithium bis(trimethylsilyl)amide (a 1 mol/L tetrahydrofuran solution,41.1 mL. 41.1 mmol) was added in an argon atmosphere at 4° C. to asolution of the[(1α,3α,4α)-(3,4-difluorocyclopentyl)methyl]triphenylphosphonium iodide(20.3 g, 40 mmol) synthesized in Reference Example 1 in anhydroustetrahydrofuran (70 mL), and the resultant mixture was stirred for 1hour at about the same temperature. Next, a solution of ethyl glyoxylate(4.24 g, 41.5 mmol) in anhydrous tetrahydrofuran (50 mL) was added at 4°C., and the resultant mixture was stirred at room temperature for 24hours. Next, water (20 mL) was added at 4° C., then 1 mol/L hydrochloricacid aqueous solution was added, and the organic layer was concentratedunder reduced pressure. The obtained residue was extracted with ethylacetate. The organic layer was washed with saturated brine. The washedorganic layer was dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The obtained residue was isolatedand purified by silica gel column chromatography (ethylacetate:hexane=1:4) to give 5.25 g of the title compound as a paleyellow oily substance.

MS (EI⁺) m/z: 204 (M⁺).

HRMS (EI⁺) for C₁₀H₁₄F₂O₂ (M⁺): calcd., 204.0962; found, 204.0942.

¹H NMR (400 MHz, CDCl₃) 51.29 (t, J=7.1 Hz, 3H), 1.74-1.90 (m, 2H),2.26-2.42 (m, 2H), 3.84-3.98 (m, 1H), 4.16 (q, J=7.1 Hz, 2H), 4.80-4.90(m, 1H), 4.92-5.02 (m, 1H), 5.74 (dd, J=11.6, 1.2 Hz, 1H), 6.22 (dd,J=11.0, 9.8 Hz, 1H).

Reference Example 23 Ethyl(Z)-2-bromo-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylate

Bromine (1.19 mL, 23.2 mmol) was added in an argon atmosphere at −6° C.to a solution of the compound (5.00 g, 24.5 mmol) of Reference Example22 in carbon tetrachloride (15 mL), and the resultant mixture was thenstirred for 7 hours at room temperature. The reaction mixture wasconcentrated under reduced pressure, and anhydrous dichloromethane (40mL) was added to the obtained residue. Next, in an argon atmosphere,triethylamine (4.10 mL, 29.4 mmol) was added at 4° C., and the resultantmixture was stirred for 12 hours at room temperature. Water was added tothe reaction mixture, whereby separate layers formed. Then, the aqueouslayer was extracted with dichloromethane, and the obtained organiclayers are collected. The combined mixture was washed with 1 mol/Lhydrochloric acid aqueous solution, and then washed with saturatedbrine. The washed mixture was dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The obtained residue wasisolated and purified by silica gel column chromatography (ethylacetate:hexane=1:5) to give 7.33 g of the title compound as a colorlessoily substance.

MS (EI⁺) m/z: 282 (M⁺).

HRMS (EI⁺) for C₁₀H₁₃BrF₂O₂ (M⁺): calcd., 282.0067; found, 282.0081.

¹H NMR (400 MHz, CDCl₃) δ1.34 (t, J=7.3 Hz, 3H), 1.86-2.02 (m, 2H),2.28-2.44 (m, 2H), 3.08-3.20 (m, 1H), 4.29 (q, J=7.3 Hz, 2H), 4.84-4.94(m, 1H), 4.96-5.06 (m, 1H), 7.29 (d, J=9.2 Hz, 1H).

Reference Example 24 Ethyl(E)-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]acrylate

Pinacolato diboron (88.0 mg, 0.35 mmol),1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (8 mg), andpotassium acetate (98.0 mg, 1.00 mmol) were added to a solution of4-bromomethyl sulfonyl benzene (79.0 mg, 0.33 mmol) in dimethylformamide(1 mL), and the resultant mixture was stirred in an argon atmosphere for80 minutes at 120° C. Next, ethyl(Z)-2-bromo-3-[(1α,3α,4α)-3,4-difluorocyclopentyl]acrylate (100.0 mg,0.33 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride(10 mg), and 2 mol/L sodium carbonate aqueous solution (1 mL) wereadded, and the resultant mixture was stirred in an argon atmosphere for2 hours at 80° C. Water was added to the reaction mixture. Extractionwas carried out with ethyl acetate, and the organic layer was washedwith water and then saturated brine. The washed organic layer was driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The obtained residue was isolated and purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:1) to give 39.3 g of thetitle compound.

Reference Example 25(E)-3-[(1β,3α,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]-N-(thiazol-2-yl)acrylamide(Comparative Compound 1)

Using the [(1β,3β,4β)-3,4-dihydroxycyclopentyl]methyl benzoate obtainedin the first step of Reference Example 1, the same reactions as in thesecond to seventh steps of Reference Example 1 were carried out tosynthesize(1β,3α,4α)-(3,4-difluorocyclopentyl)methyltriphenylphosphonium iodide.Further, the conversions of from Example 1 to Example 5 were carried outto obtained the title compound.

Reference Example 26(E)-3-[(3α,4β)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]-N-(thiozol-2-yl)acrylamide(Comparative Compound 2), and(E)-3-[(3β,4α)-3,4-difluorocyclopentyl]-2-[4-(methylsulfonyl)phenyl]-N-(thiozol-2-yl)acrylamide(Comparative Compound 3)

Using the [(1α,3α,4β)-3-fluoro-4-hydroxycyclopentyl]methyl benzoateobtained in the third step of Reference Example 1, stereo inversionbased on a Mitsunobu reaction of a hydroxyl group was carried out,followed by the same fluorination as in the fourth step of ReferenceExample 1. Then, the resultant product underwent hydrolysis of the estergroup, and oxidation of the hydroxymethyl group to convert the productinto a carboxylic acid. This carboxylic acid was condensed with(S)-4-phenyloxazolidinone, the diastereomer was then separated, theasymmetric auxiliary group was removed, the resultant product was thenreduced to methanol compound, and the reactions of from the sixth andsubsequent steps of Reference Example 1 were carried out in order toobtain the title compound.

Test Example 1 GK Activity Measurement

The GK activity was determined not by direct measurement of the amountof glucose-6-phosphate produced by the enzyme reaction but bymeasurement of the amount of NADH produced by aglucose-6-dehydrogenase-coupled reaction.

(Preparation of Recombinant GK) Cloning of Human Hepatic GK and HumanPancreas GK and Acquisition of Recombinant Proteins

Based on a human hepatic GK sequence available from GeneBank (AccessionNumber: NM_(—)033507) and a human pancreas GK sequence (AccessionNumber: NM_(—)000162), PCR cloning was performed using Pyrobest DNAPolymerase (product of Takara Bio Inc.) with human hepatic cDNA (productof Clontech Laboratories, Inc.) and human pancreas cDNA (product ofClontech Laboratories, Inc.) used as templates. The enzymes wereexpressed in a soluble form in E. coli as His-tagged fusion proteins(tagged with six His residues at the C-terminus. The E. coli cells weresonicated and centrifuged, and the supernatant was collected. Thecollected supernatant was purified by metal chelate affinitychromatography.

After purification, the enzymes were stored in 12.5 mM HEPES (pH 7.3),75 mM KCl, 0.5 mM MgCl₂, 0.5 mM DTT, 2.5 mM glucose, and 50% glycerol at−80° C.

(Measurement of GK Activity)

The assay was performed at 25° C. using a half-area flat-bottom 96-wellplate (product of Costar). The incubation mixture was prepared such thatthe final mixture contained a 25 mM HEPES buffer solution (pH 7.1)(product of Invitrogen Corporation), 25 mM KCl (product of Wako PureChemical Industries, Ltd.), 2 mM MgCl₂ (product of Wako Pure ChemicalIndustries, Ltd.), 5 mM D-glucose (product of Wako Pure ChemicalIndustries, Ltd.), 1 mM ATP (product of Roche), 1 mM NAD (product ofSigma), 1 mM dithiothreitol (product of Wako Pure Chemical Industries,Ltd.), 5 Unit/mL G6PDH (product of Sigma), 0.1% BSA (product of Sigma),GK, and a test compound or 5% DMSO.

The test compound was dissolved in DMSO in advance, and 2 μL of theprepared solution was added to 20 μL of a solution containing the HEPESbuffer solution (pH 7.1), KCl, MgCl₂, D-glucose, ATP, NAD, anddithiothreitol. Subsequently, 18 μL of a solution containing the G6PDH,BSA, and recombinant GK was added to the mixture to initiate thereaction. The GK was added such that an increase in absorbance perminute in the presence of 5% DMSO was between 0.002 to 0.003. After thereaction was initiated, the increase in absorbance at 340 nm wasmeasured for 15 minutes using a SPECTRAmax 190 microplatespectrophotometer (product of Molecular Devices Corporation), and theactivity was evaluated using the increase in the first 10 minutes.

When the compounds 1A, 26A, 27A, 31A, 44A, 49A, 1B, 2B, 4B, 31B, 38B,41B, 53B, 21B, and 26B of the present invention were added in an amountof 10 μM, the effect of activating the human hepatic GK was found to be200% or more that of a well not containing the compounds. Especially, inthe compound 1A of the present invention, EC₅₀ was shown to be 1 μM orless. On the other hand, in the comparative compound 1-3, each EC₅₀found to be more than 10 μM.

Test Example 2 Hypoglycemia Activity Test

The effects of the test compounds on blood glucose levels were measuredusing ICR mice (male, 7 to 9 weeks of age, Charles River LaboratoriesJapan, Inc.). Each of the compounds was dissolved in a mixture ofGelucire 44/14 (trade name, product of Gattefosse) and PEG 400 (60:40),and was orally administered to the animal after 2-hour fasting period(30 mg/kg, 10 mL/kg). Blood was collected from the caudal veinimmediately before the administration (Pre value) and 0.5, 2, and 4hours after the administration using a blood-collecting tube coated withdipotassium ethylenediaminetetraacetate and was centrifuged (4° C.,3,600×g, 3 minutes) to obtain a plasma sample.

Each sample was diluted five-fold with physiological saline, and theblood glucose level was measured using Glucose CII-Test Wako (tradename, product of Wako Pure Chemical Industries, Ltd.). Morespecifically, the samples and a glucose standard solution (100 mg/dL)(obtained by diluting a glucose standard solution (200 mg/dL) two-foldwith physiological saline) were placed in the wells of a flat-bottom96-well plate in an amount of 10 μL/well, and 150 μL of a color reagentwas added to each well. The plate was left to stand at 37° C. for 5minutes to allow color development. The measurement of OD at 505 nm wasperformed using En Vision 2103 Multilabel Reader (trade name, product ofPerkinElmer Inc.). The reduction ratio of the blood glucose level ateach sampling point relative to the Pre value was determined, and aglucose reduction ratio (the average of the determined reduction ratios)was computed.

In the compounds 1A, 26A, 27A, 31A, 44A, 1B, 2B, 11B, 12B, 21B, 26B,62A, 31B, 79B, 103B, 108B, 4B, 38B, 53B, 46A, 58A, and 41B of thepresent invention, the glucose reduction ratio was found to be 35% ormore. Especially, in the compound 1A of the present invention, thereduction ratio was shown to be 50% or more. On the other hand, in thecomparative compound 1-3, the each reduction ratio found to be less than30%.

Test Example 3 Dosage Dependence of Hypoglycemia and Insulin SecretionPromotion Tests

The effects of the test compounds on blood glucose levels and insulinsecretion were measured using ICR mice (male, 7 to 9 weeks of age,Charles River Laboratories Japan, Inc.). Each of the compounds wasdissolved in a mixture of Gelucire 44/14 (trade name, product ofGattefosse) and PEG 400 (60:40), and was orally administered to theanimal after a 2-hour fasting period (30 mg/kg, 10 mL/kg). Blood wascollected from the caudal vein immediately before the administration(Pre value) and 0.5, 1, 2, and 4 hours after the administration using ablood-collecting tube coated with dipotassiumethylenediaminetetraacetate and was centrifuged (4° C., 3,600×g, 3minutes) to obtain a plasma sample.

Each sample was diluted five-fold with physiological saline, and theblood glucose level was measured using Glucose CII-Test Wako (tradename, product of Wako Pure Chemical Industries, Ltd.). Morespecifically, the samples, physiological saline, and a glucose standardsolution (100 mg/dL) (obtained by diluting a glucose standard solution(200 mg/dL) two-fold with physiological saline) were placed in the wellsof a flat-bottom 96-well plate in an amount of 10 μL/well, respectively,and 150 μL of a color reagent was added to each well. The plate was leftto stand at 37° C. for 5 minutes to allow color development. Themeasurement of OD at 505 nm was performed using En Vision 2103 Multilabel Reader (trade name, product of PerkinElmer Inc.). The glucose areaunder the curve_(0.5-4 hr) (Glucose AUC_(0.5-4 hr)) was calculated fromthe blood glucose level at each blood collection point.

The insulin concentration was measured using an undiluted solution ofeach sample with a Morinaga insulin measurement kit (trade name, productof Morinaga Institute of Biological Science Inc.). The insulin areaunder the curve_(0.5-4 hr) (Insulin AUC_(0.5-4 hr)) was calculated fromthe insulin level at each blood collection point.

Test Example 4 Effects on Abnormal Glucose Tolerance of Severe Diabetesdb/db Mice

The effects on the abnormal glucose tolerance of severe diabetes db/dbmice were tested by a method based on the Fyfe method (Diabetologia.2007 June; 50 (6): 1277-87). The effects of the test compounds onabnormal glucose tolerance were measured using db/db mice (male, 7 weeksof age, Charles River Laboratories Japan, Inc.). Each of the compoundswas dissolved in a mixture of Gelucire 44/14 (trade name, product ofGattefosse) and PEG 400 (60:40), and was orally administered to theanimal after a 16 to 20-hour fasting period. A glycemic load was appliedby administering a 5 g/kg glucose solution 1 hour after administrationof the drug solution. Blood was collected from the caudal vein 1 hourbefore the drug solution administration, before the glycemic load, and0.25, 0.5, 1, 2, and 4 hours after the glycemic load using ablood-collecting tube coated with dipotassiumethylenediaminetetraacetate and was centrifuged to obtain a plasmasample. Each sample was diluted ten-fold with physiological saline, andthe blood glucose level was measured using Glucose CII Kit (trade name,product of Wako Pure Chemical Industries, Ltd.). The blood glucose levelAUC 0.25 to 4 hours after glycemic load was calculated as the “Bloodglucose after glycemic load”.

EC₅₀ and ED₅₀ were calculated using the test compound bloodconcentration (Cmax) and the dosage amount on the basis of the bloodglucose rate of decrease for each group as an index of drug efficacywhen the data for the control group was taken as 0.

Test Example 5 hERG Current Suppression Test

Using a HEK 293 cell transfected with a human ether-a-go-go-related gene(hERG), the hERG current which passed through the whole cell membraneunder a voltage clamp was recorded by a whole-cell patch clamp method.To confirm the hERG current of the cell, a depolarization pulse wasperiodically applied while maintaining the membrane potential at −80 my.After the generated current stabilized, the cell was perfused with aperfusate (applying solution) in which the test substance was dissolvedfor 10 minutes. The effects of the test substance on the hERG channelwere evaluated on the basis of the change in the tail current induced bya +20 mV depolarization pulse for 1.5 seconds followed by anotherdepolarization pulse of −50 mV for 1.5 seconds. Stimulation wasperformed at a frequency of once every 10 seconds. The test was carriedout at 34° C. The absolute value of the maximum tail current wasdetermined on the basis of the current value at the maintained membranepotential, and the rate of change (suppression rate) 10 minutes afterapplication in the maximum tail current from before application of thetest substance was calculated.

The hERG when 30 μM of the inventive compounds 1A, 12A, 44A, 18B, 31B,41B, 71B, 103B, 4B, 31A, 38B, and 68B was 50% or less in all cases.

INDUSTRIAL APPLICABILITY

The glucokinase activators of the present invention have an excellent GKactivating or hypoglycemic effect and few side effects (such as Q-Tinterval prolongation (relating to hERG current suppression) andinsulin-induced hypoglycemia) and are therefore useful aspharmaceuticals for the treatment or prevention of diabetes, obesity,and the like.

1-22. (canceled)
 23. A compound represented by the general formula (2):

(wherein R¹ and R² are each independently a hydrogen atom, a halogenatom, an amino group, a hydroxyl group, a hydroxyamino group, a nitrogroup, a cyano group, a sulfamoyl group, a C₁ to C₆ alkyl group, a C₁ toC₆ alkoxy group, a C₁ to C₆ alkylsulfanyl group, a C₁ to C₆alkylsulfinyl group, a C₁ to C₆ alkylsulfonyl group, or a C₁ to C₆alkoxy-C₁ to C₆ alkylsulfonyl group).
 24. The compound according toclaim 23, wherein R¹ is a hydrogen atom, and R² is a cyclopropylsulfonylgroup.
 25. The compound according to claim 23, wherein R¹ is a hydrogenatom, and R² is a methylsulfonyl group.